TGF-β signaling in health, disease and therapeutics
健康、疾病和治疗中的 TGF-β 信号转导

The studies on TGF-β started as early as the 1980s and have developed rapidly ever since. Although TGF-β was first found to be secreted by transformed cells,¹ it is widely produced by non-neoplastic tissues such as salivary glands, muscles, kidneys, liver, heart, brain, and embryos as well.^2,3,4 In fact, platelets have been identified as one of the most abundant sources of TGF-β among all normal tissues.⁵ The ubiquitous expression of TGF-β in health strongly indicates its critical and multiple roles in physiological conditions.
TGF-β的研究早在20世纪80年代就开始了，此后发展迅速。尽管 TGF-β 最初被发现是由转化细胞分泌的¹ ，但它也广泛由非肿瘤组织产生，如唾液腺、肌肉、肾脏、肝脏、心脏、大脑和胚胎。 ^{2 , 3 , 4}事实上，血小板已被确定为所有正常组织中最丰富的 TGF-β 来源之一。 ⁵ TGF-β 在健康中的普遍表达强烈表明其在生理条件下的关键和多重作用。

Accumulating evidence has suggested that TGF-β functions diversely among different cell types in a context-dependent manner. Generally, cell survival, metabolism, growth, proliferation, differentiation, adhesion, migration, and death are all under the regulation of TGF-β. Proper TGF-β signaling is critical to the normal functioning and homeostasis of healthy bodies while aberrant TGF-β signaling can lead to diseases of various categories. For this reason, numerous targeted therapies that can remedy dysregulated TGF-β activity have been developed with some demonstrating encouraging safety and efficacy in clinical trials.
越来越多的证据表明，TGF-β 在不同细胞类型中以环境依赖性方式发挥不同的功能。一般而言，细胞的存活、代谢、生长、增殖、分化、粘附、迁移和死亡均受TGF-β的调控。正确的 TGF-β 信号传导对于健康身体的正常功能和体内平衡至关重要，而异常的 TGF-β 信号传导则可能导致各种类型的疾病。出于这个原因，已经开发了许多可以纠正 TGF-β 活性失调的靶向疗法，其中一些疗法在临床试验中显示出令人鼓舞的安全性和有效性。

In this review, we focus on the mechanism, physiology, pathology, as well as therapeutics of TGF-β signaling, aiming to provide historical, current, and future perspectives on relevant topics.
在这篇综述中，我们重点关注 TGF-β 信号传导的机制、生理学、病理学以及治疗学，旨在提供相关主题的历史、当前和未来观点。

TGF-β was first reported in 1978 when De Larco and Todaro discovered the ‘sarcoma growth factors’ which were produced by transformed murine fibroblasts and were able to transform normal fibroblasts to anchorage-independent growth.¹ In 1981, Roberts et al. successfully isolated and purified TGF-β from non-neoplastic murine tissues,³ while at about the same time, Moses et al. independently accomplished the purification and characterization of the cytokine as well.⁶ Both groups also noticed that this relatively acid- and heat-stable polypeptide required disulfide bonds for activity and was sensitive to disulfide-reducing agent dithiothreitol. In 1983, studies by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels indicated that the 25,000-dalton TGF-β molecule in humans was actually composed of two 12,500-dalton subunits cross-linked by disulfide bonds.^7,8 Two years later, the amino-acid sequence of human TGF-β1, the first known TGF-β isoform, was revealed by Derynck et al. through direct protein sequencing and complementary deoxyribonucleic acid (DNA) cloning.² The sequencing established that the 112-amino-acid-long TGF-β1 monomer is initially synthesized as the C-terminal segment of a 390-amino-acid-long precursor polypeptide.² By the time of 1988, researchers had realized that TGF-β generally remained non-covalently associated with the N-terminal segment of its precursor when it was secreted.^9,10 TGF-β cannot bind to its receptors with its receptor-binding site being masked in this inactive form, however, certain treatments such as acidification could convert latent TGF-β complex into active TGF-β ligand.¹¹ In addition, the other two TGF-β isoforms in mammals, TGF-β2 and TGF-β3, were respectively identified in 1987¹² and 1988.^13,14 Although the three TGF-β isoforms are encoded by three different genes, their mature ligands show strong conservation of amino acid sequences.
TGF-β 于 1978 年首次报道，当时 De Larco 和 Todaro 发现了由转化的小鼠成纤维细胞产生的“肉瘤生长因子”，并且能够将正常成纤维细胞转化为不依赖贴壁的生长。 ¹ 1981 年，罗伯茨等人。成功地从非肿瘤性鼠组织中分离和纯化了 TGF-β， ³大约在同一时间，Moses 等人。并独立完成了细胞因子的纯化和表征。 ⁶两个小组还注意到，这种对酸和热相对稳定的多肽需要二硫键才能发挥活性，并且对二硫键还原剂二硫苏糖醇敏感。 1983年，十二烷基硫酸钠-聚丙烯酰胺凝胶电泳研究表明，人体中25,000道尔顿的TGF-β分子实际上是由两个通过二硫键交联的12,500道尔顿的亚基组成。 ^{7 , 8}两年后，Derynck 等人揭示了人类 TGF-β1（第一个已知的 TGF-β 同工型）的氨基酸序列。通过直接蛋白质测序和互补脱氧核糖核酸（DNA）克隆。 ²测序确定，112 个氨基酸长的 TGF-β1 单体最初是作为 390 个氨基酸长的前体多肽的 C 端片段合成的。 ²到 1988 年，研究人员意识到 TGF-β 在分泌时通常与其前体的 N 末端片段保持非共价结合。^{9 , 10} TGF-β 不能与其受体结合，其受体结合位点以这种非活性形式被掩盖，但是，某些治疗（例如酸化）可以将潜在的 TGF-β 复合物转化为活性 TGF-β 配体。 ¹¹此外，哺乳动物中的另外两种 TGF-β 同工型 TGF-β2 和 TGF-β3 分别于 1987 年¹²和 1988 年被鉴定。 ^{13 , 14}尽管这三种 TGF-β 同工型由三个不同的基因编码，但它们的成熟配体显示出氨基酸序列的强烈保守性。

The effects of TGF-β signaling in cell proliferation,^15,16 cell differentiation,^17,18 embryonic development,¹⁹ wound healing,²⁰ immune regulation,^21,22 tissue fibrosis,^23,24 and tumor development^25,26 have been studied shortly after the discovery of the cytokine. Meanwhile, the receptors in TGF-β signaling known as TGF-β receptor I (TβRI) and TβRII were also identified and characterized in the 1980s.^27,28,29 But it was not until the discovery of signaling mediators small (Sma) in Caenorhabditis elegans and mothers against decapentaplegic (Mad) in Drosophila melanogaster that the homologous small mothers against decapentaplegic (SMAD) proteins were identified as the canonical signal transducers of TGF-β signaling in humans in 1996.^30,31,32 Since then, the development of TGF-β research has been largely accelerated. In recent times, as studies on TGF-β signaling in both health and disease going deeper and further, a lot of TGF-β-targeting therapies have been developed and assessed for the treatment of various diseases,^{33,34,35,36,37,38,39} revealing a promising future for the studies in this area (Fig. 1).
TGF-β信号传导对细胞增殖、 ^{15、16细胞}分化^{、 17、18}胚胎发育、 ¹⁹伤口愈合、 ²⁰免疫调节^{、 21、22}组织纤维化^{、 23、24}和肿瘤发展^25、26的影响已被短期研究细胞因子被发现后。与此同时，TGF-β 信号传导中的受体，即 TGF-β 受体 I (TβRI) 和 TβRII 也在 20 世纪 80 年代被鉴定和表征。 ^{27 , 28 , 29}但直到发现了秀丽隐杆线虫中的小信号介导物（Sma）和果蝇中的抗十五麻痹母蛋白（Mad），同源的小母抗十五麻痹蛋白（SMAD）才被确定为典型的信号转导子。 1996 年人类中 TGF-β 信号转导的研究进展。 ^{30 , 31 , 32}从那时起，TGF-β 研究的发展大大加速。近年来，随着对健康和疾病中 TGF-β 信号传导的研究越来越深入，许多 TGF-β 靶向疗法已被开发和评估用于治疗各种疾病， ^{33 , 34 , 35 , 36 , 37、38、39揭示了}该领域研究的广阔前景（图1 ） 。

History of research on TGF-β signaling
TGF-β信号研究的历史

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During the biosynthesis of TGF-β, the precursor undergoes post-translational processing to become a latent complex which is the secretory form of TGF-β. The latent TGF-β complex still requires further activation to eventually become a mature cytokine before it can trigger signal transduction in cells (Fig. 2).
在 TGF-β 的生物合成过程中，前体经过翻译后加工成为潜在复合物，即 TGF-β 的分泌形式。潜在的TGF-β复合物仍需要进一步激活才能最终成为成熟的细胞因子，然后才能触发细胞内的信号转导（图2 ）。

Biosynthesis and activation of TGF-β. Each TGF-β monomer is initially synthesized as a precursor polypeptide. In the endoplasmic reticulum, TGF-β precursors lose their signal peptides and dimerize through disulfide bonds. The dimers then transit into the Golgi where they are cleaved by protease furin into mature cytokine segments and latency-associated peptides (LAPs) to form small latent complexes (SLCs). The secreted SLCs can further link to latent TGF-β-binding proteins (LTBPs) which target them into the extracellular matrix (ECM) for storage, or they can link to glycoprotein-A repetitions predominant protein (GARP) or leucine-rich repeat-containing protein 33 (LRRC33) which tethers them to the cell surface. Numerous factors such as acids, bases, reactive oxygen species (ROS), thrombospondin-1 (TSP-1), certain proteases, and integrins can release the mature cytokines from the latent complexes and thus are known as TGF-β activators
TGF-β 的生物合成和激活。每个 TGF-β 单体最初都是作为前体多肽合成的。在内质网中，TGF-β前体失去信号肽并通过二硫键形成二聚体。然后二聚体进入高尔基体，在那里它们被弗林蛋白酶裂解成成熟的细胞因子片段和潜伏相关肽（LAP），从而形成小的潜伏复合物（SLC）。分泌的 SLC 可以进一步连接到潜在的 TGF-β 结合蛋白 (LTBP)，将其靶向细胞外基质 (ECM) 进行储存，或者它们可以连接到糖蛋白 A 重复优势蛋白 (GARP) 或富含亮氨酸的重复蛋白含有将它们束缚在细胞表面的蛋白质 33 (LRRC33)。许多因子，如酸、碱、活性氧 (ROS)、血小板反应蛋白-1 (TSP-1)、某些蛋白酶和整合素，可以从潜在复合物中释放成熟的细胞因子，因此被称为 TGF-β 激活剂

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TGF-β biosynthesis and latency
TGF-β生物合成和潜伏期

Each TGF-β monomer is initially synthesized as a precursor polypeptide composed of a mature cytokine as its C-terminal segment, a signal peptide at the N-terminus, and a latency-associated peptide (LAP) in between.² The signal peptide leads the precursor into the endoplasmic reticulum lumen and promptly gets removed. The remainder of the precursor then dimerizes through three disulfide bonds and transits into the Golgi where it gets cleaved between the mature cytokine and LAP by protease furin.⁴⁰ However, the cytokine segment is still unable to bind its receptors after the cleavage, for it remains associated with LAP in a non-covalent way that masks its receptor-binding site and forms a small latent complex (SLC).⁴¹ In most cases, LAP is linked to latent TGF-β-binding protein (LTBP) through a disulfide bond, making the SLC into a large latent complex (LLC) when secreted.⁴² LTBP can further bind to fibrillin to target the LLC into the extracellular matrix (ECM) for storage.⁴³ Alternatively, LAP can also form disulfide linkage with leucine-rich repeat-containing protein 32 (LRRC32) or LRRC33 to tether SLC to the cell surface. Unlike LTBP which is widely expressed by many cell types, LRRC32, also known as glycoprotein-A repetitions predominant protein (GARP), is specifically detected in regulatory T cells (Tregs), platelets, and endothelium,⁴⁴ whereas high expression of LRRC33 is found in macrophages, dendritic cells (DCs), and B cells.⁴⁵
每个 TGF-β 单体最初合成为前体多肽，由成熟细胞因子作为其 C 端片段、N 端信号肽和其间的潜伏相关肽 (LAP) 组成。 ²信号肽引导前体进入内质网腔并迅速被去除。然后前体的其余部分通过三个二硫键二聚化并转移到高尔基体中，在那里它被蛋白酶弗林蛋白酶在成熟细胞因子和 LAP 之间裂解。 ⁴⁰然而，细胞因子片段在裂解后仍然无法结合其受体，因为它仍然以非共价方式与 LAP 结合，从而掩盖其受体结合位点并形成小的潜在复合物 (SLC)。 ⁴¹在大多数情况下，LAP 通过二硫键与潜在的 TGF-β 结合蛋白 (LTBP) 连接，使 SLC 在分泌时形成一个大的潜在复合物 (LLC)。 ⁴² LTBP 可以进一步与原纤维蛋白结合，将 LLC 靶向细胞外基质 (ECM) 进行储存。 ⁴³另外，LAP 还可以与富含亮氨酸重复序列的蛋白 32 (LRRC32) 或 LRRC33 形成二硫键，将 SLC 束缚在细胞表面。与在多种细胞类型中广泛表达的 LTBP 不同，LRRC32（也称为糖蛋白 A 重复优势蛋白 (GARP)）在调节性 T 细胞 (Treg)、血小板和内皮细胞中特异性检测到， ⁴⁴而 LRRC33 则高表达存在于巨噬细胞、树突状细胞 (DC) 和 B 细胞中。 ⁴⁵

TGF-β activation TGF-β激活

The bioactivity of TGF-β is based on ligand-receptor interaction which requires the exposure of its receptor-binding site. Thus, the activation of TGF-β represents the release of mature cytokine from the latent complex. Numerous factors have been identified as TGF-β activators as introduced below. Notably, integrin-dependent activation is so far the best described and likely the most important mechanism, while TGF-β activation mediated by acids, bases, reactive oxygen species (ROS), thrombospondin-1 (TSP-1), proteases, and other TGF-β activators is collectively known as integrin-independent activation.
TGF-β的生物活性基于配体-受体相互作用，这需要暴露其受体结合位点。因此，TGF-β的激活代表成熟细胞因子从潜在复合物中的释放。如下所述，许多因子已被鉴定为 TGF-β 激活剂。值得注意的是，整合素依赖性激活是迄今为止描述最好的，也可能是最重要的机制，而 TGF-β 激活则由酸、碱、活性氧 (ROS)、血小板反应蛋白-1 (TSP-1)、蛋白酶和其他酶介导。 TGF-β激活剂统称为整合素非依赖性激活。

TGF-β activation by integrins
整合素激活 TGF-β

Integrins are heterodimeric transmembrane receptors each consisting of an α-subunit and a β-subunit. TGF-β activation by integrins requires the binding of the integrins to an RGD sequence in the LAP of TGF-β1 and TGF-β3. Therefore, latent TGF-β2 without the RGD motif is excluded from integrin-dependent activation.⁴⁶
整合素是异二聚体跨膜受体，每个受体由α亚基和β亚基组成。整联蛋白激活 TGF-β 需要整联蛋白与 TGF-β1 和 TGF-β3 的 LAP 中的 RGD 序列结合。因此，没有 RGD 基序的潜在 TGF-β2 被排除在整合素依赖性激活之外。 ⁴⁶

Among all integrins, αVβ6 and αVβ8 integrins are the best studied TGF-β activators. The expression of αVβ6 integrin is nearly restricted to epithelial cells and is upregulated in response to morphogenesis, wounding, inflammation, and tumorigenesis.⁴⁷ In contrast, αVβ8 integrin is widely expressed by epithelial cells,⁴⁸ fibroblasts,⁴⁹ macrophages,⁵⁰ DCs,⁵¹ Tregs,⁵² and different kinds of tumor cells.⁵³ The lack of αVβ6 and αVβ8 integrin activity reproduces the phenotypes of TGF-β1- and TGF-β3-null mice, indicating the central importance of integrin-dependent activation.^54,55
在所有整合素中，αVβ6 和 αVβ8 整合素是研究最多的 TGF-β 激活剂。 αVβ6 整合素的表达几乎仅限于上皮细胞，并且在形态发生、受伤、炎症和肿瘤发生时上调。 ⁴⁷相比之下，αVβ8 整合素广泛表达于上皮细胞、 ⁴⁸成纤维细胞、 ⁴⁹巨噬细胞、 ^{50 种}DC、 ^{51 种}Tregs、 ^{52 种}和不同种类的肿瘤细胞。 ⁵³缺乏 αVβ6 和 αVβ8 整合素活性会重现 TGF-β1 和 TGF-β3 缺失小鼠的表型，表明整合素依赖性激活的核心重要性。 ^{54 , 55}

Upon binding to the RGD motif in LAP, the mechanisms by which αVβ6 and αVβ8 integrins activate TGF-β are quite different. With latent TGF-β being tethered to ECM or cell membrane (through the binding of LAP to LTBP, GARP, or LRRC33 as mentioned before) and the cytoplasmic domain of integrin β6 subunit linking to the actin cytoskeleton, αVβ6 integrin can transmit contractile force which changes the conformation of LAP to release TGF-β ligand.^56,57 However, the cytoplasmic domain of integrin β8 subunit does not link to the actin cytoskeleton. One effective mechanism for αVβ8 integrin-mediated TGF-β activation requires the proteolytic activity of membrane type 1-matrix metalloproteinase (MT1-MMP, also known as MMP14).⁴⁸ Alternatively, membrane molecules such as GARP and LRRC33 which bind and present latent TGF-β on the surface of one cell can cooperate with the αVβ8 integrin expressed on a different cell to activate TGF-β in trans.^45,58,59 A recent study reveals that upon binding to αVβ8 integrin, the flexible membrane-presented latent complex can expose the active domain of the TGF-β ligand to its receptors for binding and signaling without the need to release diffusible cytokine.⁶⁰
与 LAP 中的 RGD 基序结合后，αVβ6 和 αVβ8 整合素激活 TGF-β 的机制截然不同。由于潜在的 TGF-β 被束缚在 ECM 或细胞膜上（通过前面提到的 LAP 与 LTBP、GARP 或 LRRC33 的结合）以及整合素 β6 亚基的胞质结构域与肌动蛋白细胞骨架相连，αVβ6 整合素可以传递收缩力，改变 LAP 的构象以释放 TGF-β 配体。 ^{56 , 57}然而，整合素 β8 亚基的胞质结构域并不与肌动蛋白细胞骨架相连。 αVβ8 整合素介导的 TGF-β 激活的一种有效机制需要 1 型膜基质金属蛋白酶（MT1-MMP，也称为 MMP14）的蛋白水解活性。 ⁴⁸另外，GARP 和 LRRC33 等膜分子在一个细胞表面结合并呈递潜在的 TGF-β，可以与不同细胞上表达的 αVβ8 整合素配合，反式激活 TGF-β。 ^{45 , 58 , 59}最近的一项研究表明，与 αVβ8 整合素结合后，柔性膜呈递的潜在复合物可以将 TGF-β 配体的活性结构域暴露于其受体，进行结合和信号传导，而无需释放可扩散的细胞因子。 ⁶⁰

TGF-β activation by acids and bases
酸和碱激活 TGF-β

It has long been noticed that acidification can unmask the activity of freshly secreted TGF-β.⁶¹ Sharply defined parameters for human TGF-β activation by acids and bases show that the transition from latency of all three isoforms occurred between pH 2.5 and 4, and between pH 10 and 12.⁶² Thus, extremely acidic environments such as the microenvironments in tumor tissues and the resorption lacunae of osteoclasts are possibly conducive to local TGF-β activation.^63,64 A study on lung fibrosis even suggests that physiologic concentrations of lactic acid are sufficient enough to activate TGF-β in a pH-dependent manner.⁶⁵
人们早就注意到酸化可以揭示新分泌的 TGF-β 的活性。 ⁶¹酸和碱对人 TGF-β 激活的明确定义的参数表明，所有三种亚型的潜伏期转变发生在 pH 2.5 至 4 之间以及 pH 10 至 12 之间。 ⁶²因此，极端酸性环境（例如肿瘤中的微环境）组织和破骨细胞的吸收腔隙可能有利于局部 TGF-β 的激活。 ^{63 , 64}一项关于肺纤维化的研究甚至表明，乳酸的生理浓度足以以 pH 依赖性方式激活 TGF-β。 ⁶⁵

TGF-β activation by ROS ROS 激活 TGF-β

TGF-β1 is the only isoform that can be directly activated by ROS, for a unique methionine residue at the amino acid position 253 of its LAP is required for oxidation-triggered conformational change.⁶⁶ However, ROS can induce other TGF-β activators such as TSP-1⁶⁷ and MMPs⁶⁸ to activate all three isoforms in an indirect manner. ROS-mediated TGF-β activation prevails in tissues exposed to asbestos,^69,70 ultraviolet,⁶⁸ and ionizing radiation.⁷¹ High glucose intake can also induce ROS production and consequentially increase TGF-β activation to play roles in the development of fibrotic diseases and inflammatory diseases.^72,73 Moreover, in T cells, ROS can be elevated during apoptosis or upon stimulation by T cell receptor (TCR) and cluster of differentiation 28 (CD28) to contribute to the immunosuppression mediated by activated TGF-β.^74,75
TGF-β1 是唯一可以被 ROS 直接激活的异构体，因为其 LAP 253 位氨基酸上的独特蛋氨酸残基是氧化触发的构象变化所必需的。 ⁶⁶然而，ROS 可以诱导其他 TGF-β 激活剂，例如 TSP-1 ⁶⁷和 MMP ⁶⁸以间接方式激活所有三种亚型。 ROS 介导的 TGF-β 激活在暴露于石棉、 ^{69 、 70}紫外线、 ⁶⁸和电离辐射的组织中普遍存在。 ⁷¹高葡萄糖摄入还可以诱导 ROS 产生，从而增加 TGF-β 激活，从而在纤维化疾病和炎症性疾病的发展中发挥作用。 ^{72 , 73}此外，在 T 细胞中，ROS 在细胞凋亡期间或在受到 T 细胞受体 (TCR) 和分化簇 28 (CD28) 刺激后会升高，从而有助于激活的 TGF-β 介导的免疫抑制。 ^{74 , 75}

TGF-β activation by TSP-1
TSP-1 激活 TGF-β

TSP-1 is a multi-functional ECM protein not only abundant in platelet α-granules but also secreted by fibroblasts, endothelial cells, macrophages, T cells, and many other cell types.⁷⁶ The KRFK sequence in TSP-1 can recognize the LSKL sequence in LAP to competitively disrupt its interaction with the receptor-binding site of the TGF-β ligand. Since the LSKL sequence in LAP is conserved among TGF-β isoforms, it is suggested that the direct binding of TSP-1 to latent complex is capable of activating all three TGF-β isoforms through this protease- and cell-independent mechanism.⁷⁷ Interestingly, TSP-1 can also bind to the mature TGF-β ligand to form a complex that retains the biological activity of the cytokine.⁷⁸ ROS,⁶⁷ glucose,⁷⁹ angiotensin II,⁸⁰ hypoxia,⁸¹ wounding,⁸² inflammation,⁸³ pathogens,^84,85,86 and many other factors can all induce TSP-1 to function as a TGF-β activator in wound healing,^67,82 cardiovascular diseases,^81,86 renal diseases,⁷⁹ fibrotic diseases,^87,88 inflammatory diseases,⁸³ infectious diseases,⁸⁹ and tumors.⁹⁰
TSP-1是一种多功能ECM蛋白，不仅在血小板α颗粒中丰富，而且由成纤维细胞、内皮细胞、巨噬细胞、T细胞和许多其他细胞类型分泌。 ⁷⁶ TSP-1 中的 KRFK 序列可以识别 LAP 中的 LSKL 序列，从而竞争性破坏其与 TGF-β 配体的受体结合位点的相互作用。由于 LAP 中的 LSKL 序列在 TGF-β 同工型中是保守的，因此表明 TSP-1 与潜在复合物的直接结合能够通过这种独立于蛋白酶和细胞的机制激活所有三种 TGF-β 同工型。 ⁷⁷有趣的是，TSP-1 还可以与成熟的 TGF-β 配体结合形成复合物，保留细胞因子的生物活性。 ⁷⁸ ROS、 ⁶⁷葡萄糖、 ⁷⁹血管紧张素 II、 ⁸⁰缺氧、 ⁸¹受伤、 ⁸²炎症、 ⁸³病原体^{、 84、85、86和}许多其他因素都可以诱导 TSP-1 在伤口愈合中充当 TGF-β 激活剂， ^{67 、 82}心血管疾病、 ^{81 、 86}肾脏疾病、 ⁷⁹纤维化疾病、 ^{87 、 88}炎症性疾病、 ⁸³传染病、 ⁸⁹和肿瘤。 ⁹⁰

TGF-β activation by proteases
蛋白酶激活 TGF-β

Many proteases have been proved capable of directly activating TGF-β in vitro. However, the function of an individual protease seems redundant in vivo, as deficiency of a single species generally leads to no significant signs of impaired TGF-β activation.⁹¹ Among these proteases, MMPs such as MMP-2, MMP-9, and MMP-13 are conducive to the TGF-β activation in wound healing,⁹² cardiovascular diseases,⁹³ renal diseases,⁹⁴ fibrotic diseases,⁹⁵ and tumors.⁹⁶ Interestingly, although the activation by MMPs works for all three TGF-β isoforms, latent TGF-β2 and TGF-β3 appear much more sensitive to MMP-9 treatment than latent TGF-β1.⁹⁶ Moreover, a serine protease known as plasmin plays an important role in the TGF-β activation mediated by macrophages^97,98 and endothelial cells.^99,100
许多蛋白酶已被证明能够在体外直接激活TGF-β。然而，单个蛋白酶的功能在体内似乎是多余的，因为单个物种的缺陷通常不会导致 TGF-β 激活受损的明显迹象。 ⁹¹在这些蛋白酶中，MMP-2、MMP-9 和 MMP-13 等 MMP 有利于伤口愈合、 ⁹²心血管疾病、 ⁹³肾脏疾病、 ⁹⁴纤维化疾病、 ⁹⁵和肿瘤中的 TGF-β 激活。 ⁹⁶有趣的是，尽管 MMP 的激活作用适用于所有三种 TGF-β 同工型，但潜在的 TGF-β2 和 TGF-β3 似乎对 MMP-9 治疗比潜在的 TGF-β1 更敏感。 ⁹⁶此外，一种称为纤溶酶的丝氨酸蛋白酶在巨噬^{细胞97、98}和内皮细胞介导的 TGF-β 激活中发挥着重要作用。 ^{99 , 100}

TGF-β signal is transmitted into the cells by TβRI (also known as activin receptor-like kinase 5, ALK5) and TβRII both of which are enzyme-linked receptors with dual specificity of serine/threonine kinase and tyrosine kinase. Studies have revealed that TGF-β1 and TGF-β3 bind TβRII prior to TβRI due to higher affinity, while TGF-β2 binds poorly to both receptors.^12,101,102 TβRIII, also known as β-glycan, lacks the motifs to directly mediate TGF-β signal transduction. However, TβRIII is able to bind TGF-β especially TGF-β2 with high affinity and thus acts as a co-receptor that presents the ligand to the receptors and further enhances their binding.^{101,103,104,105,106,107} The ligand-receptor interaction subsequently activates the intracellular signaling of TGF-β through a canonical pathway and several non-canonical pathways.
TGF-β信号通过TβRI（也称为激活素受体样激酶5，ALK5）和TβRII传递到细胞中，这两种受体都是具有丝氨酸/苏氨酸激酶和酪氨酸激酶双重特异性的酶联受体。研究表明，由于亲和力较高，TGF-β1 和 TGF-β3 在 TβRII 之前先与 TβRII 结合，而 TGF-β2 与这两种受体的结合都很差。 ^{12 , 101 , 102} TβRIII，也称为β-聚糖，缺乏直接介导TGF-β信号转导的基序。然而，TβRIII能够以高亲和力结合TGF-β尤其是TGF-β2，因此充当共受体，将配体呈递给受体并进一步增强它们的结合。 ^{101 , 103 , 104 , 105 , 106 , 107}配体-受体相互作用随后通过经典途径和几个非经典途径激活TGF-β的细胞内信号传导。

Canonical TGF-β signaling
典型的 TGF-β 信号传导

The canonical TGF-β signaling is mediated by transcription factors SMADs and thus is also known as the SMAD signaling. Notably, the canonical pathway is under the regulation of various factors that can control the intensity and manner of cellular responses at different levels (Fig. 3).
典型的 TGF-β 信号传导由转录因子 SMAD 介导，因此也称为 SMAD 信号传导。值得注意的是，经典途径受到多种因素的调节，这些因素可以在不同水平上控制细胞反应的强度和方式（图3 ）。

Canonical TGF-β signaling. TGF-β can initially bind to its co-receptor TGF-β receptor III (TβRIII) or directly bind to its receptor TβRII which subsequently recruits TβRI to form a TGF-β-TβRI-TβRII complex. TβRII then actives TβRI through phosphorylation, leading to its dissociation with signaling inhibitor FK506-binding protein 1A (FKBP12) and interaction with signaling effectors receptor-activated SMADs (R-SMADs). R-SMADs which are presented to TβRI by adaptor protein SMAD anchor for receptor activation (SARA) get activated through phosphorylation and undergo oligomerization with common-partner SMAD (co-SMAD). The SMAD oligomers then translocate into the nucleus where they function as transcription factors (TFs), mediating the transcriptional activation or repression of target genes by binding to specific DNA sequences known as SMAD-binding elements (SBEs) and generally in cooperation with other TFs as well as transcriptional cofactors. In this way, TGF-β signaling can activate the expression of inhibitory SMADs (I-SMADs) which in turn function to attenuate the transcriptional regulation mediated by TGF-β signaling through several mechanisms. Moreover, many protein kinases (PKs), protein phosphatases (PPs), and (E3) ubiquitin ligases can also modulate canonical TGF-β signaling through various post-translational modifications of SMADs. (TFBS, TF-binding site)
典型的 TGF-β 信号传导。 TGF-β 最初可以与其共受体 TGF-β 受体 III (TβRIII) 结合，或直接与其受体 TβRII 结合，后者随后招募 TβRI 形成 TGF-β-TβRI-TβRII 复合物。然后，TβRII 通过磷酸化激活 TβRI，导致其与信号传导抑制剂 FK506 结合蛋白 1A (FKBP12) 解离，并与信号传导效应器受体激活的 SMAD (R-SMAD) 相互作用。 R-SMAD 通过接头蛋白 SMAD 受体激活锚 (SARA) 呈递给 TβRI，通过磷酸化被激活，并与共同伙伴 SMAD (co-SMAD) 发生寡聚化。然后 SMAD 寡聚体易位到细胞核中，在细胞核中充当转录因子 (TF)，通过与称为 SMAD 结合元件 (SBE) 的特定 DNA 序列结合并通常与其他 TF 配合来介导靶基因的转录激活或抑制，如以及转录辅助因子。通过这种方式，TGF-β信号传导可以激活抑制性SMADs (I-SMADs)的表达，而抑制性SMADs进而通过多种机制减弱TGF-β信号传导介导的转录调节。此外，许多蛋白激酶 (PK)、蛋白磷酸酶 (PP) 和 (E3) 泛素连接酶也可以通过 SMAD 的各种翻译后修饰来调节经典 TGF-β 信号传导。 （TFBS，TF 结合位点）

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TGF-β-activated SMAD signaling
TGF-β 激活 SMAD 信号传导

TGF-β ligand initially binds to TβRII monomer to promote its homodimerization or directly binds to pre-existing TβRII homodimer to recruit TβRI for assembly.^{108,109,110,111} This forms a heteromeric TGF-β-TβRI-TβRII complex in which low-affinity TβRI requires high-affinity TβRII to bind TGF-β ligand and constitutively active TβRII requires phosphorylating TβRI to transduce intracellular signal.¹¹² The phosphorylation of TβRI occurs in its juxtamembrane GS domain at several serine and threonine residues, triggering conformational changes that transform the GS domain from a site that binds the signaling inhibitor known as immunophilin FK506-binding protein 1A (FKBP12) into a binding site for the signaling effectors known as receptor-activated SMADs (R-SMADs).¹¹³
TGF-β配体最初与TβRII单体结合以促进其同二聚化，或直接与预先存在的TβRII同二聚体结合以募集TβRI进行组装。 ^{108 , 109 , 110 , 111}这形成异聚 TGF-β-TβRI-TβRII 复合物，其中低亲和力 TβRI 需要高亲和力 TβRII 才能结合 TGF-β 配体，而组成型活性 TβRII 需要磷酸化 TβRI 来转导细胞内信号。 ¹¹² TβRI 的磷酸化发生在其近膜 GS 结构域的几个丝氨酸和苏氨酸残基处，引发构象变化，将 GS 结构域从结合信号抑制剂（称为亲免素 FK506 结合蛋白 1A (FKBP12)）的位点转变为亲免素 FK506 结合蛋白 1A (FKBP12) 的结合位点。信号传导效应器称为受体激活 SMAD (R-SMAD)。 ¹¹³

R-SMADs, including SMAD2 and SMAD3, consist of a globular Mad homology 1 (MH1) domain at the N-terminus, a globular MH2 domain at the C-terminus, and a highly flexible long linker region in between. R-SMADs are retained in cytoplasm and presented to TβRI by the adaptor protein known as SMAD anchor for receptor activation (SARA).¹¹⁴ The R-SMAD MH2 domain then gets phosphorylated at two serine residues in the extreme C-terminal SXS motif by the TβRI kinase domain which is located immediately downstream of the TβRI GS domain.¹¹³ Activated R-SMADs undergo homo-oligomerization or hetero-oligomerization through their MH2 domains upon phosphorylation, and they can also oligomerize with SMAD4, the common-partner SMAD (co-SMAD) which lacks the SXS motif for phosphorylation by TβRI kinase. Notably, studies have suggested that SMAD heterotrimers containing two R-SMADs and one SMAD4 are likely more common and stable than other SMAD oligomers.^{115,116,117,118,119} Although different SMAD oligomers can vary in function, they all act to regulate the transcription of target genes by binding to DNA after translocating into the nucleus. The MH1 domains of SMAD4, SMAD3, and a specific SMAD2 splicing variant recognize the nucleic acid sequence GTCT or its reverse complement AGAC in double-stranded DNA which are known as the canonical SMAD-binding elements (SBEs).¹²⁰ Other SBEs such as the 5GC SBEs including GGCGC and GGCCG have also been discovered, indicating a relatively loose DNA-binding specificity of the SMAD oligomers.¹²¹ However, the binding to a single SBE is so weak that SMAD oligomers generally require interacting with replications of SBE copies as well as other DNA-binding sequence-specific transcription factors to function.^119,120,122 In fact, many SBE repeats are enriched at the binding sites for SMAD-interacting transcription factors, exactly increasing the binding accessibility, specificity, and affinity of SMAD oligomers associated with specific transcription factors.^123,124,125 Despite a large number of SMAD-interacting transcription factors indicating a huge amount of potential gene targets for canonical TGF-β signaling, the dominant effects are generally determined by the master transcription factors in specific cell types and contexts which contribute to the complexity and variability of cellular responses to TGF-β.¹²⁵ 重试    错误原因

Regulation of SMAD signaling by inhibitory SMADs (I-SMADs) 重试    错误原因

TGF-β and many other factors can induce the expression of SMAD6 and SMAD7 which function to inhibit TGF-β signaling and thus are known as I-SMADs.^126,127 Unlike R-SMADs, I-SMADs lack the N-terminal MH1 domain and the C-terminal SXS motif, however, they retain the C-terminal MH2 domain which can competitively bind to activated receptor TβRI to inhibit the phosphorylation of R-SMADs.^128,129 Through some extra mechanisms, SMAD7 confers greater abilities in suppressing TGF-β signaling than SMAD6 does.¹³⁰ For example, SMAD7 recruits E3 ubiquitin ligases such as SMAD ubiquitination regulatory factors (SMURFs) and neural precursor cell expressed, developmentally downregulated 4-like (NEDD4L) to TβRI, R-SMADs, and co-SMAD to mediate the proteasomal and lysosomal degradation of these TGF-β signaling components.^{131,132,133,134,135} SMAD7 can also trigger the dephosphorylation of TβRI by recruiting protein phosphatase 1 (PP1) to the receptor.¹³⁶ Moreover, with its MH2 domain, SMAD7 can oligomerize with R-SMADs to compete with co-SMAD¹³³ and can bind to specific DNA sequences to disrupt the formation of the transcriptional SMAD-DNA complex.¹³⁷ Taken together, TGF-β signaling induces I-SMADs to form a negative feedback loop of itself.
TGF-β和许多其他因子可以诱导SMAD6和SMAD7的表达，其功能是抑制TGF-β信号传导，因此被称为I-SMAD。 ^{126 , 127}与 R-SMAD 不同，I-SMAD 缺乏 N 端 MH1 结构域和 C 端 SXS 基序，但保留了 C 端 MH2 结构域，可以竞争性地与激活的受体 TβRI 结合，抑制 R 的磷酸化-SMAD。 ^{128 , 129}通过一些额外的机制，SMAD7 比 SMAD6 具有更强的抑制 TGF-β 信号传导的能力。 ¹³⁰例如，SMAD7 招募 E3 泛素连接酶，例如 SMAD 泛素化调节因子 (SMURF) 和神经前体细胞表达的、发育下调的 4-like (NEDD4L) 至 TβRI、R-SMAD 和 co-SMAD，以介导蛋白酶体和溶酶体降解这些 TGF-β 信号传导成分。 ^{131 , 132 , 133 , 134 , 135} SMAD7 还可以通过将蛋白磷酸酶1 (PP1)募集至受体来触发TβRI的去磷酸化。 ¹³⁶此外，凭借其 MH2 结构域，SMAD7 可以与 R-SMAD 寡聚，与 co-SMAD 竞争¹³³ ，并且可以结合特定的 DNA 序列，破坏转录 SMAD-DNA 复合物的形成。 ¹³⁷总之，TGF-β 信号传导诱导 I-SMAD 形成自身的负反馈循环。

Regulation of SMAD signaling by transcriptional cofactors
转录辅助因子对 SMAD 信号传导的调节

Transcriptional cofactors are actively recruited to the transcriptional SMAD complex to regulate its activity. Notably, many of these transcriptional cofactors have histone modification activity and thus enable TGF-β signaling to trigger epigenetic changes. Histone acetyltransferases (HATs) such as p300, cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein (CBP), p300/CBP-associated factor (PCAF), and general control non‐repressed protein 5 (GCN5) act as the transcriptional coactivators of SMADs by increasing the accessibility to DNA.^{138,139,140,141} The interaction between p300/CBP and doubly phosphorylated R-SMADs requires SMAD4 for stabilization and is critical for SMAD-mediated transcriptional activation. Other SMAD coactivators include melanocyte-specific gene 1 (MSG1),¹⁴² zinc finger E-box-binding homeobox 1 (ZEB1),^143,144 and the histone methyltransferase (HMT) known as SET domain-containing protein 7 (SETD7).¹⁴⁵ Contrary to HATs, histone deacetylases (HDACs) generally act as the transcriptional corepressors of SMADs by decreasing the accessibility to DNA. SMAD3 can directly recruit HDAC4 and HDAC5 to gene promoters to inhibit the function of transcription factors via histone deacetylation.¹⁴⁶ SMADs can also associate with HDACs through interaction with other corepressors such as TGF-β-induced factor (TGIF),¹⁴⁷ ecotropic viral integration site 1 (EVI1),^148,149 Sloan-Kettering Institute proto-oncogene (SKI),^150,151,152 as well as SKI-related novel gene N (SNO).¹⁵³ Other transcriptional corepressors of SMADs include cellular-myelocytomatosis viral oncogene (MYC),¹⁵⁴ SMAD nuclear-interacting protein 1 (SNIP1),¹⁵⁵ ZEB2,^143,156 and HMTs such as suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain bifurcated 1 (SETDB1) which can both trigger the methylation of histone 3 lysine 9 (H3K9) at gene promoters.^157,158
转录辅助因子被积极招募到转录 SMAD 复合物中以调节其活性。值得注意的是，许多转录辅助因子具有组蛋白修饰活性，从而使 TGF-β 信号传导能够触发表观遗传变化。组蛋白乙酰转移酶 (HAT)，例如 p300、环磷酸腺苷 (cAMP) 反应元件结合蛋白 (CREB) 结合蛋白 (CBP)、p300/CBP 相关因子 (PCAF) 和一般控制非抑制蛋白 5 (GCN5) ）通过增加 DNA 的可及性，充当 SMAD 的转录共激活剂。 ^{138 , 139 , 140 , 141} p300/CBP 和双磷酸化 R-SMAD 之间的相互作用需要 SMAD4 来稳定，并且对于 SMAD 介导的转录激活至关重要。其他 SMAD 共激活剂包括黑素细胞特异性基因 1 (MSG1)、 ¹⁴²锌指 E 盒结合同源框 1 (ZEB1) ^{、 143、144}和被称为含 SET 结构域的蛋白 7 (SETD7) 的组蛋白甲基转移酶 (HMT)。 ¹⁴⁵与 HAT 相反，组蛋白脱乙酰酶 (HDAC) 通常通过降低 DNA 的可及性来充当 SMAD 的转录辅阻遏物。 SMAD3可以直接将HDAC4和HDAC5招募到基因启动子处，通过组蛋白脱乙酰化来抑制转录因子的功能。^{第146章​​151、152以及}SKI相关新基因N(SNO)。^第153章SMAD 的其他转录辅阻遏物包括细胞骨髓细胞瘤病毒癌基因 (MYC)、^{第 154 章}SMAD 核相互作用蛋白 1 (SNIP1)、^{第 155 章}ZEB2、^{第 143 章、第 156 章和}HMT，例如杂色抑制因子 3-9 同源物 1 (SUV39H1) 和 SET结构域分叉 1 (SETDB1) 均可触发基因启动子处组蛋白 3 赖氨酸 9 (H3K9) 的甲基化。^{157 , 158}

Regulation of SMAD signaling by SMAD modifications
通过 SMAD 修饰调节 SMAD 信号传导

Post-translational modifications can also regulate the functions of SMADs. Apart from TβRI kinase which phosphorylates R-SMADs in their C-terminal SXS motif to mediate their activation, many other protein kinases such as mitogen-activated protein kinase kinase kinase 1 (MAPKKK1),¹⁵⁹ p38 MAPK,¹⁶⁰ c-Jun N-terminal kinase (JNK),¹⁶¹ extracellular signal-regulated kinase (ERK),^162,163,164 rat sarcoma (RAS) homolog (Rho)-associated coiled-coil-containing protein kinase (ROCK),¹⁶⁰ glycogen synthase kinase (GSK)-3β,^165,166,167 calcium/calmodulin-dependent protein kinase II (CAMK2),¹⁶⁸ protein kinase C (PKC),¹⁶⁹ PKG,¹⁷⁰ and several cyclin-dependent kinases (CDKs)^167,171,172 can phosphorylate R-SMADs as well as co-SMAD at many different sites to enhance or attenuate SMAD activity. Meanwhile, the various phosphorylation of SMADs can be reversed by phosphatases. Several nuclear phosphatases known as the small C-terminal domain phosphatases (SCPs) can specifically dephosphorylate the linker region and MH1 domain of R-SMADs,^173,174 whereas protein phosphatase, magnesium/manganese-dependent 1A (PPM1A),¹⁷⁵ myotubularin-related protein 4 (MTMR4),¹⁷⁶ and protein phosphatase 2A (PP2A)¹⁷⁷ catalyze the dephosphorylation of the C-terminal SXS motif to terminate the signaling and promote the dissociation and cytoplasmic localization of SMADs.
翻译后修饰也可以调节 SMAD 的功能。除了磷酸化 R-SMAD C 端 SXS 基序以介导其激活的 TβRI 激酶外，还有许多其他蛋白激酶，如丝裂原激活蛋白激酶激酶 1 (MAPKKK1)、 ¹⁵⁹ p38 MAPK、 ¹⁶⁰ c-Jun N 端^第161章细胞外信号调节激酶（ERK），^{第162章，第163章，第164章}大鼠肉瘤（RAS）同源物（Rho）相关卷曲螺旋蛋白激酶（ROCK），^第160章糖原合酶激酶（GSK）- 3β ^{、 165、166、167钙}/钙调蛋白依赖性蛋白激酶 II (CAMK2)、 ¹⁶⁸蛋白激酶 C (PKC)、 ¹⁶⁹ PKG、 ¹⁷⁰和几种细胞周期蛋白依赖性激酶 ( ^{CDK ) 167、171、172}可以磷酸化 R-SMAD以及在许多不同位点的 co-SMAD 以增强或减弱 SMAD 活性。同时，SMADs的各种磷酸化可以被磷酸酶逆转。 几种被称为小 C 端结构域磷酸酶 (SCP) 的核磷酸酶可以特异性地使 R-SMAD 的接头区域和 MH1 结构域去磷酸化， ^{173 , 174}而蛋白磷酸酶，镁/锰依赖性 1A (PPM1A)， ¹⁷⁵肌管蛋白相关蛋白 4 (MTMR4)、 ¹⁷⁶和蛋白磷酸酶 2A (PP2A) ¹⁷⁷催化 C 端 SXS 基序的去磷酸化，以终止信号传导并促进 SMAD 的解离和细胞质定位。

Furthermore, SMADs can be ubiquitinated and deubiquitinated respectively by E3 ubiquitin ligases and deubiquitylating enzymes (DUBs). The E3 ubiquitin ligases that can mediate SMAD ubiquitination include SMURFs,^{135,178,179,180} NEDD4L,^134,181 WW domain-containing proteins (WWPs),^182,183,184 really interesting new gene (RING) finger protein 111 (RNF111),¹⁸⁵ C-terminus of heat shock protein (HSP) 70-interacting protein (CHIP),¹⁸⁶ itchy (ITCH) E3 ubiquitin ligase,¹⁸⁷ and S-phase kinase-associated protein (SKP)-cullin-F-box (SCF) E3 ubiquitin ligase complex.^188,189 The ubiquitination generally leads to the proteasomal degradation of SMADs, but in some cases, it also exerts non-degradative effects on SMAD activity.¹⁹⁰ Notably, the degradative ubiquitination of R-SMADs by NEDD4L requires the phosphorylation of the R-SMAD linker by CDK8/9 and GSK-3 in sequence to create binding sites for the E3 ubiquitin ligase.^171,181,191
此外，SMAD 可以分别被 E3 泛素连接酶和去泛素化酶 (DUB) 泛素化和去泛素化。能够介导 SMAD 泛素化的 E3 泛素连接酶包括 SMURF ^{、 135、178、179、180 NEDD4L 、 134、181含}WW 结构域的蛋白（WWP） ^{、 182、183、184真正}有趣的新基因（RING）指蛋白 111（RNF111） )、 ¹⁸⁵热休克蛋白 (HSP) C 末端 70 相互作用蛋白 (CHIP)、 ¹⁸⁶痒 (ITCH) E3 泛素连接酶、 ¹⁸⁷和 S 期激酶相关蛋白 (SKP)-cullin-F-box (SCF) ) E3 泛素连接酶复合物。 ^{188 , 189}泛素化通常会导致 SMAD 的蛋白酶体降解，但在某些情况下，它也会对 SMAD 活性产生非降解作用。 ¹⁹⁰值得注意的是，NEDD4L 对 R-SMAD 的降解性泛素化需要 CDK8/9 和 GSK-3 按顺序磷酸化 R-SMAD 接头，以创建 E3 泛素连接酶的结合位点。 ^{171 , 181 , 191}

Non-canonical TGF-β signaling
非典型 TGF-β 信号传导

Apart from the SMAD-dependent pathway, TGF-β can also signal through SMAD-independent pathways to activate ERK signaling, Rho guanosine triphosphatase (GTPase) signaling, p38 MAPK signaling, JNK signaling, nuclear factor-κB (NF-κB) signaling, phosphatidylinositol 3-kinase (PI3K)/AKR mouse thymoma proto-oncogene (AKT) signaling, as well as Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. These non-canonical TGF-β signaling pathways are involved in an extensive range of cellular events, greatly expanding the participation of TGF-β signaling in health and disease (Fig. 4).
除了 SMAD 依赖性途径外，TGF-β 还可以通过 SMAD 独立途径发出信号，激活 ERK 信号、Rho 鸟苷三磷酸酶 (GTPase) 信号、p38 MAPK 信号、JNK 信号、核因子-κB (NF-κB) 信号、磷脂酰肌醇 3-激酶 (PI3K)/AKR 小鼠胸腺瘤原癌基因 (AKT) 信号传导，以及 Janus 激酶 (JAK)/信号转导器和转录激活子 (STAT) 信号传导。这些非常规的TGF-β信号通路参与了广泛的细胞事件，极大地扩展了TGF-β信号传导在健康和疾病中的参与（图4 ）。

Non-canonical TGF-β signaling. TGF-β can signal through non-canonical pathways to activate extracellular signal-regulated kinase (ERK) signaling, rat sarcoma (RAS) homolog (Rho)-guanosine triphosphatase (GTPase) signaling, p38 mitogen-activated protein kinase (MAPK) signaling, c-Jun N-terminal kinase (JNK) signaling, nuclear factor-κB (NF-κB) signaling, phosphatidylinositol 3-kinase (PI3K)/AKR mouse thymoma proto-oncogene (AKT) signaling, as well as Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. These non-canonical TGF-β signaling pathways are actively involved in an extensive range of cellular events. (RAF, RAS-associated factor; MEK, MAPK/ERK kinase; ROCK1, Rho-associated coiled-coil-containing protein kinase 1; LIMK2, LIM domain kinase 2; TRAF, tumor necrosis factor (TNF) receptor-associated factor; TAK1, TGF-β-activated kinase 1; MKK, MAPK kinase; IKK, NF-κB inhibitor (IκB) kinase; GSK-3β, glycogen synthase kinase-3β; MTOR, mechanistic target of rapamycin; FOXO, forkhead box O; S6K, S6 kinase; 4EBP1, 4E-binding protein 1)
非典型 TGF-β 信号传导。 TGF-β 可以通过非经典途径发出信号，激活细胞外信号调节激酶 (ERK) 信号、大鼠肉瘤 (RAS) 同源物 (Rho)-鸟苷三磷酸酶 (GTPase) 信号、p38 丝裂原激活蛋白激酶 (MAPK) 信号、 c-Jun N 末端激酶 (JNK) 信号传导、核因子-κB (NF-κB) 信号传导、磷脂酰肌醇 3-激酶 (PI3K)/AKR 小鼠胸腺瘤原癌基因 (AKT) 信号传导以及 Janus 激酶 (JAK) /信号转导子和转录激活子 (STAT) 信号传导。这些非经典 TGF-β 信号通路积极参与广泛的细胞事件。 （RAF，RAS 相关因子；MEK，MAPK/ERK 激酶；ROCK1，Rho 相关卷曲螺旋蛋白激酶 1；LIMK2，LIM 结构域激酶 2；TRAF，肿瘤坏死因子 (TNF) 受体相关因子；TAK1 、 TGF-β 激活激酶 1；IKK、NF-κB 抑制剂 (IκB) 激酶；MTOR、雷帕霉素的机制靶点； S6 激酶；4EBP1、4E 结合蛋白 1)

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TGF-β-activated ERK signaling
TGF-β 激活的 ERK 信号传导

As a dual-specificity kinase, TβRI can phosphorylate at its tyrosine residues to activate ERK signaling upon TGF-β stimulation.¹⁹² In this case, TβRI with tyrosine kinase activity initially phosphorylates the adapter protein known as sarcoma (SRC) homology and collagen A (SHCA) which subsequently forms a complex with growth factor receptor-bound protein 2 (GRB2) and son of sevenless homolog (SOS). The SHCA-GRB2-SOS complex then initiates a canonical MAPK signaling cascade which involves the sequential activation of RAS, the MAPKKK known as RAS-associated factor (RAF), the MAPKK known as MAPK/ERK kinase (MEK), and eventually, the ERK MAPK. Activated ERK is known to regulate various biological events including cell survival, proliferation, differentiation, adhesion, migration, as well as metabolism, and is implicated in a spectrum of diseases such as developmental disorders, chronic inflammation, neurodegeneration, obesity, and cancers.^193,194
作为一种双特异性激酶，TβRI 可以在其酪氨酸残基处磷酸化，从而在 TGF-β 刺激下激活 ERK 信号传导。 ¹⁹²在这种情况下，具有酪氨酸激酶活性的 TβRI 首先磷酸化称为肉瘤 (SRC) 同源物的接头蛋白和胶原蛋白 A (SHCA)，随后与生长因子受体结合蛋白 2 (GRB2) 和七同源物的儿子形成复合物 (求救）。然后，SHCA-GRB2-SOS 复合物启动典型的 MAPK 信号级联，其中依次激活 RAS、称为 RAS 相关因子 (RAF) 的 MAPKKK、称为 MAPK/ERK 激酶 (MEK) 的 MAPKK，以及最终激活ERK 映射。已知激活的 ERK 可调节各种生物事件，包括细胞存活、增殖、分化、粘附、迁移以及代谢，并与发育障碍、慢性炎症、神经退行性疾病、肥胖和癌症等一系列疾病有关。 ^{193 , 194}

TGF-β-activated Rho GTPase signaling
TGF-β 激活的 Rho GTPase 信号转导

Rho GTPases such as RHO, RAS-related C3 botulinum toxin substrate 1 (RAC1), and cell division cycle 42 (CDC42) play a central role in the organization and dynamics of the actin cytoskeleton. They are activated by guanine nucleotide exchange factors (GEFs) through the exchange of a bound GDP for GTP.¹⁹⁵ TGF-β can trigger RHO activation in a rapid SMAD-independent manner or by inducing a GEF known as neuroepithelial cell transforming 1 (NET1) through SMAD and MEK/ERK pathways.^{196,197,198,199,200} RHO then activates its key effector ROCK1 which further mediates the phosphorylation of LIM domain kinase 2 (LIMK2). Activated LIMK2 subsequently phosphorylates cofilin to inhibit its function as a constitutive actin-depolymerizing factor, leading to the reorganization of the actin cytoskeleton in the end.^201,202,203 Additionally, TGF-β-triggered RHO/ROCK1 signaling can contribute to ERK phosphorylation,^204,205 and besides RHO, TGF-β can also activate the signaling of other Rho GTPases such as RAC1²⁰² and CDC42.²⁰⁶ Besides the regulation of cell morphogenesis, adhesion, and movement, Rho GTPase signaling is also known to participate in transcriptional regulation, cell cycle progression, vesicular trafficking, and pathological processes such as fibrosis, inflammation, wound repair, and tumor development.^207,208
RHO GTP 酶，例如 RHO、RAS 相关的 C3 肉毒毒素底物 1 (RAC1) 和细胞分裂周期 42 (CDC42) 在肌动蛋白细胞骨架的组织和动力学中发挥着核心作用。它们通过鸟嘌呤核苷酸交换因子 (GEF) 将结合的 GDP 交换为 GTP 来激活。 ¹⁹⁵ TGF-β 可以以不依赖 SMAD 的方式快速触发 RHO 激活，或者通过 SMAD 和 MEK/ERK 途径诱导称为神经上皮细胞转化 1 (NET1) 的 GEF。 ^{196 , 197 , 198 , 199 , 200} RHO 然后激活其关键效应子 ROCK1 ，进一步介导 LIM 结构域激酶 2 (LIMK2) 的磷酸化。激活的 LIMK2 随后磷酸化 cofilin，抑制其作为组成型肌动蛋白解聚因子的功能，最终导致肌动蛋白细胞骨架的重组。 ^{201 、 202 、 203}此外，TGF-β 触发的 RHO/ROCK1 信号传导可促进 ERK 磷酸化， ^{204 、 205}并且除了 RHO 之外，TGF-β 还可激活其他 Rho GTP 酶（例如 RAC1 ²⁰²和 CDC42）的信号传导。 ²⁰⁶除了调节细胞形态发生、粘附和运动外，Rho GTPase 信号传导还参与转录调节、细胞周期进程、囊泡运输以及纤维化、炎症、伤口修复和肿瘤发展等病理过程。 ^{207 , 208}

TGF-β-activated p38, JNK, and NF-κB signaling
TGF-β 激活的 p38、JNK 和 NF-κB 信号转导

TGF-β can activate the signaling of another two MAPKs known as p38 and JNK through a receptor kinase-independent mechanism which is different from that of ERK signaling. TGF-β-activated TβR complex can recruit tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and TRAF6 to trigger their lysine 63 (K63)-linked polyubiquitination. With E3 ubiquitin ligase activity, polyubiquitinated TRAF then attaches the polyubiquitin chain on the MAPKKK known as TGF-β-activated kinase 1 (TAK1) which subsequently gets activated and phosphorylates several MAPKKs (MKKs).^209,210,211 As a result, MKK3 and MKK6 specifically trigger the activation of p38 while MKK4 mediates the phosphorylation of both p38 and JNK. TGF-β-activated Rho GTPases such as RHOA, RAC1, and CDC42 can also contribute to p38 and JNK activation.^{204,212,213,214,215,216} Both the two MAPKs regulate a series of biological events to respond to all kinds of environmental and intracellular stresses, meanwhile, they engage actively in embryonic development, metabolic regulation, neuronal functions, immunological actions, as well as tumor development.^{217,218,219,220}
TGF-β可以通过与ERK信号传导不同的受体激酶独立机制激活另外两种MAPK（p38和JNK）的信号传导。 TGF-β 激活的 TβR 复合物可以招募肿瘤坏死因子 (TNF) 受体相关因子 4 (TRAF4) 和 TRAF6，以触发其赖氨酸 63 (K63) 连接的多聚泛素化。借助 E3 泛素连接酶活性，多聚泛素化 TRAF 将多聚泛素链附着在称为 TGF-β 激活激酶 1 (TAK1) 的 MAPKKK 上，随后该激酶被激活并磷酸化多个 MAPKK (MKK)。 ^{209 , 210 , 211}因此，MKK3 和 MKK6 特异性触发 p38 的激活，而 MKK4 介导 p38 和 JNK 的磷酸化。 TGF-β 激活的 Rho GTP 酶（例如 RHOA、RAC1 和 CDC42）也可促进 p38 和 JNK 激活。 ^{204 , 212 , 213 , 214 , 215 , 216}两种MAPK均调节一系列生物事件以应对各种环境和细胞内应激，同时积极参与胚胎发育、代谢调节、神经元功能、免疫作用、以及肿瘤的发展。 ^{217 , 218 , 219 , 220}

Additionally, TGF-β-activated TRAF/TAK1 signaling, RHO/ROCK1 signaling, and PI3K/AKT signaling can also lead to the phosphorylation of NF-κB inhibitor (IκB) kinase (IKK).^{221,222,223,224} Activated IKK then triggers the phosphorylation of IκB which subsequently gets polyubiquitinated and degraded while releasing active NF-κB for nuclear translocation.²²¹ NF-κB as a transcription factor can regulate hundreds of genes involved in cell survival, proliferation, metabolism, and immunity in particular.^225,226,227
此外，TGF-β激活的TRAF/TAK1信号传导、RHO/ROCK1信号传导和PI3K/AKT信号传导也可导致NF-κB抑制剂(IκB)激酶(IKK)的磷酸化。 ^{221 , 222 , 223 , 224}激活的 IKK 然后触发 IκB 的磷酸化，随后 IκB 被多泛素化并降解，同时释放活性 NF-κB 以进行核易位。 ²²¹ NF-κB 作为转录因子可以调节数百个与细胞存活、增殖、代谢、特别是免疫相关的基因。 ^{225 , 226 , 227}

TGF-β-activated PI3K/AKT signaling
TGF-β 激活 PI3K/AKT 信号转导

The TβR complex can activate the lipid kinase PI3K upon TGF-β stimulation, either via the kinase activity of TβRI or through the recruitment of TRAF6, which polyubiquitylates PI3K regulatory subunit p85α independent of the receptor kinase.^228,229 Activated PI3K then phosphorylates phosphoinositide phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3) which further triggers the phosphorylation of AKT.^228,230 Activated AKT targets plenty of substrates, including mechanistic target of rapamycin (MTOR),^231,232 GSK-3β,²³³ and several forkhead box O (FOXO) transcription factors.²³⁴Among them, MTOR is the most common downstream effector of AKT, and ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) are the best-characterized downstream effectors of MTOR. In general, the consequences of PI3K/AKT signaling include diverse cellular responses such as survival, metabolism, growth, proliferation, and differentiation.²³⁵
TβR 复合物可以在 TGF-β 刺激下通过 TβRI 的激酶活性或通过 TRAF6 的募集来激活脂质激酶 PI3K，TRAF6 不依赖于受体激酶而多泛素化​​ PI3K 调节亚基 p85α。 ^{228 , 229}激活的 PI3K 然后将磷酸肌醇磷脂酰肌醇-4,5-二磷酸 (PIP2) 磷酸化为磷脂酰肌醇-3,4,5-三磷酸 (PIP3)，这进一步触发 AKT 的磷酸化。 ^{228 、 230}激活的 AKT 靶向大量底物，包括雷帕霉素 (MTOR) 的机械靶标、 ^{231 、 232} GSK-3β、 ²³³和几种叉头盒 O (FOXO) 转录因子。 ²³⁴其中，MTOR 是 AKT 最常见的下游效应子，核糖体蛋白 S6 激酶 (S6K) 和真核起始因子 4E 结合蛋白 1 (4EBP1) 是特征最明显的 MTOR 下游效应子。一般来说，PI3K/AKT 信号传导的后果包括多种细胞反应，例如生存、代谢、生长、增殖和分化。 ²³⁵

TGF-β-activated JAK/STAT signaling
TGF-β 激活的 JAK/STAT 信号传导

TGF-β is found to induce JAK1 and JAK2 activation respectively in hepatic stellate cells (HSCs) and fibroblasts. In these cases, activated JAK triggers the phosphorylation of STAT3 which functions to mediate the fibrogenic effects of TGF-β, including increased cell proliferation, myofibroblast (MF) differentiation, ECM production, α-smooth muscle actin (α-SMA) expression, and stress fiber formation.^236,237,238 Like other signaling pathways, JAK/STAT signaling can also drive many physiological and pathological events, including development, metabolism, immunity, wounding, and cancers.²³⁹
研究发现 TGF-β 分别在肝星状细胞 (HSC) 和成纤维细胞中诱导 JAK1 和 JAK2 激活。在这些情况下，激活的 JAK 会触发 STAT3 的磷酸化，STAT3 的作用是介导 TGF-β 的纤维化作用，包括增加细胞增殖、肌成纤维细胞 (MF) 分化、ECM 产生、α-平滑肌肌动蛋白 (α-SMA) 表达和应力纤维的形成。 ^{236 , 237 , 238}与其他信号传导途径一样，JAK/STAT 信号传导也可以驱动许多生理和病理事件，包括发育、代谢、免疫、受伤和癌症。 ²³⁹

In physiological conditions, TGF-β signaling is greatly required by multiple biological processes and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis (Fig. 5).
在生理条件下，多种生物过程非常需要TGF-β信号传导，并且对于胚胎发育、伤口愈合、组织稳态和免疫稳态尤其重要（图5 ）。

TGF-β signaling in health. TGF-β signaling plays a critical role in physiological conditions. a During embryonic development, TGF-β regulates cell differentiation, epithelial/endothelial-mesenchymal transition (EMT/EndMT), and apoptosis to ensure proper histogenesis and organogenesis. b TGF-β promotes wound healing by participating in inflammation, re-epithelialization, angiogenesis, and fibroblast activation. c TGF-β is indispensable for tissue homeostasis as it generally suppresses cell proliferation and induces cell apoptosis through various mechanisms. d TGF-β functions to suppress the activity of multiple immunocompetent cells while inducing the phenotypes of several immune immunosuppressive cells to maintain immune homeostasis. (SMC, smooth muscle cell; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; TIMP tissue inhibitor of MMP, PAI plasminogen activator inhibitor, CDK cyclin-dependent kinase, CKI CDK inhibitor, ID inhibitor of DNA binding, MYC cellular-myelocytomatosis viral oncogene, CDC25A cell division cycle 25A, BCL-2 B-cell lymphoma-2, BAX BCL-2-associated X protein, BIM BCL-2-interacting mediator of cell death, BCL-XL BCL-extra-large, GADD45β growth arrest and DNA damage-inducible β, SHIP sarcoma (SRC) homology 2 (SH2) domain-containing inositol 5’-phosphatase, TIEG TGF-β-inducible early gene, CTL cytotoxic T lymphocyte, Th T helper, Treg regulatory T cell, Breg regulatory B cell, NK natural killer, DC dendritic cell)
健康中的 TGF-β 信号传导。 TGF-β信号传导在生理条件下发挥着关键作用。 a在胚胎发育过程中，TGF-β 调节细胞分化、上皮/内皮-间质转化 (EMT/EndMT) 和细胞凋亡，以确保正确的组织发生和器官发生。 b TGF-β 通过参与炎症、上皮再生、血管生成和成纤维细胞激活来促进伤口愈合。 c TGF-β 对于组织稳态是不可或缺的，因为它通常通过各种机制抑制细胞增殖并诱导细胞凋亡。 d TGF-β 的作用是抑制多种免疫活性细胞的活性，同时诱导多种免疫免疫抑制细胞的表型，以维持免疫稳态。 （SMC，平滑肌细胞；VEGF，血管内皮生长因子；MMP，基质金属蛋白酶；TIMP MMP 组织抑制剂，PAI 纤溶酶原激活剂抑制剂，CDK 细胞周期蛋白依赖性激酶，CKI CDK 抑制剂，ID DNA 结合抑制剂，MYC 细胞骨髓细胞增多症病毒癌基因、CDC25A 细胞分裂周期 25A、BCL-2 B 细胞淋巴瘤-2、BAX BCL-2 相关 X 蛋白、BIM BCL-2 细胞死亡相互作用介体、BCL-XL BCL-超大、GADD45β 生长阻滞和 DNA 损伤诱导型 β、SHIP 肉瘤 (SRC) 同源性 2 (SH2) 结构域含肌醇 5'-磷酸酶、TIEG TGF-β 诱导型早期基因、CTL 细胞毒性 T 淋巴细胞、Th T 辅助细胞、Treg 调节性 T 细胞、 Breg 调节性 B 细胞、NK 自然杀伤细胞、DC 树突状细胞）

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Embryonic development 胚胎发育

In situ hybridization and immunohistochemical staining reveal overlapping but distinct expression patterns of the three TGF-β isoforms at different developmental stages of murine embryos. TGF-β is expressed in nearly all kinds of embryonic tissues such as heart, vessels, lungs, kidneys, liver, gut, bones, teeth, cartilages, muscles, skin, thymus, thyroid, suprarenal glands, salivary glands, nervous system, and craniofacial tissues.^{19,240,241,242,243,244} In particular, mesenchymal and epithelial components undergoing organogenesis and morphogenesis which involve active cell differentiation and epithelial-mesenchymal interactions generally express high levels of TGF-β.^{19,240,241,242,243}
原位杂交和免疫组织化学染色揭示了小鼠胚胎不同发育阶段三种 TGF-β 亚型重叠但不同的表达模式。 TGF-β在几乎所有类型的胚胎组织中表达，如心脏、血管、肺、肾、肝脏、肠道、骨骼、牙齿、软骨、肌肉、皮肤、胸腺、甲状腺、肾上腺、唾液腺、神经系统和颅面组织。 ^{19、240、241、242、243、244特别地，经历涉及}活跃细胞分化和上皮-间质相互作用的器官发生和形态发生的间充质和上皮成分通常表达高水平的TGF-β。 ^{19、240、241、242、243​​​​}

TGF-β has a significant impact on cell differentiation. Studies on Xenopus embryos reveal that TGF-β can induce mesoderm formation which is a primary patterning event in early vertebrate development.^245,246 TGF-β can further regulate the development of hemangioblasts from mesoderm as well as subsequent differentiation of hematopoietic stem and progenitor cells (HSPCs) to participate in hematopoiesis and vasculogenesis.^{240,247,248,249,250} Mesenchymal stem cells (MSCs) which are derived from the mesoderm as well also respond actively to TGF-β signaling during their differentiation into several connective tissue cell lineages such as osteocytes, chondrocytes, myocytes, and adipocytes.^251,252 TGF-β inhibits osteogenic differentiation by inducing the nuclear translocation of β-catenin and repressing the transcriptional activity of core-binding factor subunit α-1 (CBFA1) in a SMAD3-dependent manner.^252,253 TGF-β-induced SMAD signaling also inhibits myogenesis and adipogenesis by respectively repressing the transcriptional activity of myogenic differentiation (MYOD) family members^{254,255,256,257} and CCAAT/enhancer-binding proteins (C/EBPs).^17,258,259 However, the differentiation of MSCs into smooth muscle cells (SMCs) is promoted by TGF-β through mechanisms involving the activation of SMAD signaling, RHO signaling, and NOTCH signaling.²⁶⁰ Moreover, TGF-β stimulates chondrogenesis by inducing mesenchymal cells to differentiate into chondrocytes and produce cartilage-specific proteoglycan and type II collagen.^18,261,262 As for other cell types, TGF-β signaling also regulates the differentiation and development in epidermis,²⁶³ lungs,^264,265 kidneys,²⁶⁶ pancreas,^267,268 teeth,²⁶⁹ and nervous system.^{270,271,272,273,274,275,276}
TGF-β对细胞分化有显着影响。对非洲爪蟾胚胎的研究表明，TGF-β 可以诱导中胚层形成，这是早期脊椎动物发育中的主要模式事件。 ^{245 , 246} TGF-β可以进一步调节中胚层成血管细胞的发育以及随后的造血干细胞和祖细胞(HSPC)的分化以参与造血和血管生成。 ^{240 , 247 , 248 , 249 , 250}源自中胚层的间充质干细胞 (MSC) 在分化为骨细胞、软骨细胞、肌细胞和脂肪细胞等多种结缔组织细胞谱系的过程中也会对 TGF-β 信号做出积极反应。 ^{251 , 252} TGF-β通过诱导β-连环蛋白的核转位并以SMAD3依赖性方式抑制核心结合因子亚基α-1 (CBFA1)的转录活性来抑制成骨分化。 ^{252、253 TGF} -β诱导的 SMAD 信号传导还通过分别抑制生肌分化 (MYOD ^{)家族成员254、255、256、257}和 CCAAT/增强子结合蛋白 (C/EBP) 的转录活性来抑制肌生成和脂肪生成。 ^{17 , 258 , 259}然而，TGF-β 通过涉及 SMAD 信号传导、RHO 信号传导和 NOTCH 信号传导的激活机制来促进 MSC 分化为平滑肌细胞 (SMC)。²⁶⁰此外，TGF-β 通过诱导间充质细胞分化为软骨细胞并产生软骨特异性蛋白多糖和 II 型胶原来刺激软骨形成。 ^{18 , 261 , 262}与其他细胞类型一样，TGF-β信号还调节表皮、 ²⁶³肺^{、 264、265}肾、 ²⁶⁶胰腺、 ^{267、268牙齿}、 ²⁶⁹和神经系统的分化和发育。^{270、271、272、273、274、275、276​​​​​​}

Especially for epithelial cells, TGF-β can induce a reversible de-differentiation process known as epithelial-mesenchymal transition (EMT) which is critical to embryonic development.²⁷⁷ During EMT, epithelial cells lose their cellular polarity, intercellular junctions, and epithelial markers such as E-cadherin, but turn to acquire mesenchymal or fibroblastic phenotype with increased cell migratory motility, ECM proteolytic activity, and expression of mesenchymal markers such as fibronectin.²⁷⁸ This process is generally mediated by transcription factors such as SNAIL, SLUG, ZEB, and TWIST, involving both SMAD-dependent and SMAD-independent pathways in the case of TGF-β signaling.^{198,200,219,230,231,232,279,280} The developmental functions of TGF-β-induced EMT have been well studied in embryonic palate formation during which the expression of TGF-β is significantly elevated.^19,243 Among the three TGF-β isoforms expressed in developing murine palate,^281,282 only TGF-β3 is indispensable to the fusion of palatal shelves which is a crucial step during palatogenesis.²⁸³ Mechanically, TGF-β3 induces the EMT of palatal midline epithelial seam (MES) cells, leading to the disintegration of the epithelium and subsequent confluence of the mesenchyme.^279,280 Interestingly, endothelial cells can undergo a similar process known as endothelial-mesenchymal transition (EndMT) which is crucial for cardiovascular development. In humans, TGF-β2 is the most potent inducer of EndMT, while TGF-β1 and TGF-β3 at least partially rely on the induction of TGF-β2 to trigger this process.²⁸⁴ Consistently, although all three TGF-β isoforms are differentially expressed during murine cardiogenesis,^{19,240,242,243,285,286,287} only TGF-β2 is obligatory to the EndMT during the endocardial cushion development in the atrioventricular canal which is necessary to valvular formation.^{288,289,290,291} Moreover, TGF-β1 and TGF-β2 can trigger EndMT in the epicardium to contribute to coronary vessel formation.^292,293 In fact, TGF-β signaling is essential to vasculogenesis in many developing tissues by promoting the proliferation and migration of endothelial cells.^19,294
特别是对于上皮细胞，TGF-β可以诱导可逆的去分化过程，称为上皮间质转化（EMT），这对胚胎发育至关重要。 ²⁷⁷在 EMT 期间，上皮细胞失去细胞极性、细胞间连接和上皮标记物（如 E-钙粘蛋白），但转而获得间充质或成纤维细胞表型，并增加细胞迁移运动、ECM 蛋白水解活性和间充质标记物（如纤连蛋白）的表达。 ²⁷⁸这一过程通常由 SNAIL、SLUG、ZEB 和 TWIST 等转录因子介导，在 TGF-β 信号转导中涉及 SMAD 依赖性和 SMAD 独立途径。 ^{198 , 200 , 219 , 230 , 231 , 232 , 279 , 280} TGF-β 诱导的 EMT 的发育功能已在胚胎腭形成过程中得到充分研究，在此期间 TGF-β 的表达显着升高。 ^{19 , 243}在发育中的小鼠上颚中表达的三种 TGF-β 亚型中， ^{281 , 282}只有 TGF-β3 对于腭架融合是不可或缺的，而腭架融合是腭发育过程中的关键步骤。 ²⁸³从机械角度来看，TGF-β3 诱导腭中线上皮缝 (MES) 细胞发生 EMT，导致上皮崩解以及随后间质的汇合。 ^{279 , 280}有趣的是，内皮细胞可以经历类似的过程，称为内皮间质转化 (EndMT)，这对心血管发育至关重要。 在人类中，TGF-β2 是 EndMT 最有效的诱导剂，而 TGF-β1 和 TGF-β3 至少部分依赖 TGF-β2 的诱导来触发这一过程。 ²⁸⁴一致地，尽管所有三种 TGF-β 亚型在小鼠心脏发生过程中^{都有差异表达， 19、240、242、243、285、286、287 ，但}在房室管心内膜垫发育过程中，只有 TGF-β2 对 EndMT 是必需的。瓣膜形成所必需的。 ^{288 , 289 , 290 , 291}此外，TGF-β1 和 TGF-β2 可以触发心外膜中的 EndMT，促进冠状血管形成。 ^{292 , 293}事实上，TGF-β 信号传导通过促进内皮细胞的增殖和迁移，对于许多发育组织中的血管生成至关重要。^{19 , 294}

Furthermore, TGF-β can induce apoptosis of unnecessary cells during embryonic development to ensure proper histogenesis and organogenesis. During murine palatogenesis, the disintegration of MES not only relies on TGF-β3-induced EMT as introduced above but also requires TGF-β3-induced apoptosis of MES cells to complete palatal confluency.²⁹⁵ In murine limb buds, highly expressed TGF-β triggers massive cell death in the mesenchyme of interdigital spaces to induce the regression of interdigital webs and the formation of free digits.^19,243,296 Endogenous TGF-β also mediates the apoptotic death of certain neuron types in chick embryos to contribute to nervous system development.²⁹⁷ Notably, TGF-β2 and TGF-β3 presenting in the central part of the developing chick retina are essentially required to trigger retinal cell apoptosis, which can create space for incoming axons of retinal ganglion cells to form optic nerve.^298,299 In mice, however, TGF-β signaling also protects retinal neurons from excessive apoptosis to ensure proper development of eyes.³⁰⁰
此外，TGF-β可以诱导胚胎发育过程中不必要的细胞凋亡，以确保适当的组织发生和器官发生。在小鼠腭发育过程中，MES的解体不仅依赖于上文介绍的TGF-β3诱导的EMT，而且还需要TGF-β3诱导MES细胞凋亡才能完成腭融合。 ²⁹⁵在小鼠肢芽中，高表达的 TGF-β 会触发指间间隙间充质的大量细胞死亡，从而诱导指间网的退化和游离指的形成。 ^{19 , 243 , 296}内源性 TGF-β 还可介导鸡胚胎中某些神经元类型的细胞凋亡，从而有助于神经系统发育。 ²⁹⁷值得注意的是，发育中的小鸡视网膜中央部分存在的 TGF-β2 和 TGF-β3 本质上是触发视网膜细胞凋亡所必需的，这可以为视网膜神经节细胞的传入轴突形成视神经创造空间。 ^{298 , 299}然而，在小鼠中，TGF-β 信号传导还可以保护视网膜神经元免于过度凋亡，以确保眼睛的正常发育。 ³⁰⁰

Wound healing 伤口愈合

Wound healing which happens after tissue injuries generally involves four orderly and overlapping stages known as hemostasis, inflammation, proliferation, and remodeling.³⁰¹ Throughout the healing of cutaneous wounds, all TGF-β isoforms and TβR types are induced in a distinct spatial and temporal pattern.^302,303 During hemostasis, platelets provide an immediate and abundant supply of TGF-β after wounding, contributing largely to subsequent healing stages by promoting the influx of inflammatory cells and fibroblasts into the wounds due to its chemotactic activity.^{302,304,305,306,307} Interestingly, many of the cell types recruited by TGF-β are also active in secreting TGF-β, leading to even higher TGF-β concentrations in the wounds. In ovine skin, all three TGF-β isoforms increase dramatically only one day after wounding, attributed to the expression by epithelial cells, endothelial cells, fibroblasts, and inflammatory cells such as neutrophils, macrophages, and lymphocytes.³⁰² During the stage of proliferation and remodeling, TGF-β is implicated in wound re-epithelialization, tissue angiogenesis, and fibroblast activation.^308,309 Upon cutaneous injury, TGF-β1 is initially expressed by all epidermal keratinocytes adjacent to the wounds but gradually gets excluded from the basal keratinocytes, corresponding to the transient block and subsequent burst of basal keratinocyte proliferation after wounding.³¹⁰ TGF-β1 also contributes to the migration of epithelial sheets at the leading edges of cutaneous wounds through the regulation of integrins and the activation of PI3K.^310,311,312 Other TGF-β isoforms such as TGF-β3 can have similar impacts on cell migration during cutaneous wound healing.³¹³ As for angiogenesis, TGF-β regulates the proliferation and migration of endothelial cells in vitro and shows potent angiogenic activity when overexpressed or directly applied in vivo.^{307,314,315,316,317,318,319,320,321} A possible mechanism of TGF-β-induced angiogenesis involves the induction of vascular endothelial growth factor (VEGF) in epithelial cells and fibroblasts.^322,323 Moreover, TGF-β can stimulate fibroblasts to proliferate and produce bioactive factors such as collagen, fibronectin, MMPs, tissue inhibitor of MMPs (TIMPs), and plasminogen activator inhibitor 1 (PAI-1) which contribute to the deposition and remodeling of wound ECM.^{304,306,307,315,317,321,324,325,326,327,328,329,330,331,332,333,334} It can also promote fibroblast-mediated wound contraction through MF differentiation and RHO activation.^335,336,337
组织损伤后发生的伤口愈合通常涉及四个有序且重叠的阶段，即止血、炎症、增殖和重塑。 ³⁰¹在皮肤伤口的愈合过程中，所有 TGF-β 同工型和 TβR 类型均以独特的空间和时间模式诱导。 ^{302 , 303}在止血过程中，血小板在受伤后立即提供充足的 TGF-β 供应，由于其趋化活性，促进炎症细胞和成纤维细胞流入伤口，从而在很大程度上促进后续的愈合阶段。 ^{302 , 304 , 305 , 306 , 307}有趣的是，TGF-β 招募的许多细胞类型也积极分泌 TGF-β ，导致伤口中的 TGF-β 浓度甚至更高。在绵羊皮肤中，所有三种 TGF-β 亚型在受伤后仅一天就急剧增加，归因于上皮细胞、内皮细胞、成纤维细胞和炎症细胞（如中性粒细胞、巨噬细胞和淋巴细胞）的表达。 ³⁰²在增殖和重塑阶段，TGF-β 参与伤口上皮再形成、组织血管生成和成纤维细胞活化。 ^{308 , 309}皮肤损伤时，TGF-β1 最初由伤口附近的所有表皮角质形成细胞表达，但逐渐从基底角质形成细胞中排除，对应于受伤后基底角质形成细胞增殖的短暂阻断和随后的爆发。³¹⁰ TGF-β1 还通过整合素的调节和 PI3K 的激活，促进皮肤伤口前缘上皮片的迁移。 ^{310、311、312其他TGF} -β 同工型（例如 TGF-β3）对皮肤伤口愈合过程中的细胞迁移也有类似的影响。 ³¹³至于血管生成，TGF-β 在体外调节内皮细胞的增殖和迁移，并且在体内过表达或直接应用时显示出有效的血管生成活性。 ^{307、314、315、316、317、318、319、320、321 TGF - β诱导的血管生成的}可能机制涉及上皮细胞和成纤维细胞中血管内皮生长因子（VEGF）的诱导。 ^{322 , 323}此外，TGF-β 可以刺激成纤维细胞增殖并产生生物活性因子，如胶原蛋白、纤连蛋白、MMP、MMP 组织抑制剂 (TIMPs) 和纤溶酶原激活剂抑制剂 1 (PAI-1)，这些因子有助于沉积和重塑伤口 ECM。 ^{304、306、307、315、317、321、324、325、326、327、328、329、330、331、332、333、334还可以通过MF分化和RHO激活促进成纤维细胞介导的伤口}收缩。^{335 , 336 , 337}

Apart from the skin, TGF-β also functions in the repair and regeneration of many other tissues. During rat liver regeneration, all TGF-β isoforms are induced in non-parenchymal cells rather than hepatocytes, which however, exhibit upregulation of all TβR types to enhance the responsiveness to TGF-β, which may help to prevent uncontrolled cell proliferation.^{338,339,340,341,342} Similarly, the marked increase in TGF-β and TβR expression following acute pancreatitis suggests the role of TGF-β signaling in pancreatic repair.^343,344,345 Upon vascular injury, TGF-β mobilizes MSCs to peripheral blood and further recruits them to the injured sites for vascular repair.³⁴⁶ As for cardiac repair after myocardial injury, TGF-β triggers the EndMT of epicardial cells, which then migrate into the injured myocardium to generate various cardiac cell types.³⁴⁷ TGF-β also plays a role in cartilage repair by stimulating proteoglycan synthesis in chondrocytes.^348,349 Moreover, after injury in the nervous system, neurons, astrocytes, microglia, as well as recruited macrophages all upregulate the expression of TGF-β which may contribute to the healing process of the nervous tissues.^350,351
除皮肤外，TGF-β 还参与许多其他组织的修复和再生。在大鼠肝脏再生过程中，所有 TGF-β 亚型均在非实质细胞而非肝细胞中诱导，然而，肝细胞表现出所有 TβR 类型的上调，以增强对 TGF-β 的反应性，这可能有助于防止不受控制的细胞增殖。 ^{338 , 339 , 340 , 341 , 342}同样，急性胰腺炎后 TGF-β 和 TβR 表达显着增加表明 TGF-β 信号传导在胰腺修复中的作用。 ^{343 , 344 , 345}血管损伤后，TGF-β 将 MSC 动员到外周血，并进一步将它们募集到损伤部位进行血管修复。 ³⁴⁶至于心肌损伤后的心脏修复，TGF-β 会触发心外膜细胞的 EndMT，然后迁移到受损的心肌中，生成各种心肌细胞类型。 ³⁴⁷ TGF-β 还通过刺激软骨细胞中的蛋白多糖合成而在软骨修复中发挥作用。 ^{348 , 349}此外，神经系统损伤后，神经元、星形胶质细胞、小胶质细胞以及招募的巨噬细胞都会上调 TGF-β 的表达，这可能有助于神经组织的愈合过程。 ^{350 , 351}

Tissue homeostasis 组织稳态

Tissue homeostasis is maintained by the balance between cell proliferation and cell death in which TGF-β acts as a key regulator.
组织稳态是通过细胞增殖和细胞死亡之间的平衡来维持的，其中 TGF-β 起着关键的调节作用。

Cell proliferation is generally driven by CDKs through a series of events collectively known as the cell cycle. For most cells, TGF-β inhibits their proliferation, or in other words, triggers their cytostasis by inducing cell cycle arrest in the gap 1 (G1) phase. In epithelial cells and glial cells, TGF-β suppresses the activity of CDKs by activating the transcription of CDK inhibitors (CKIs) such as p15 and p21 to induce cytostasis.^{352,353,354,355} The transcriptional activation of CKIs in response to TGF-β is likely mediated by SMADs in cooperation with transcription factor FOXO^355,356 or specificity protein 1 (SP1).^357,358 Notably, the SMAD-FOXO complex additionally requires transcription factor C/EBPβ for the induction of p15 but not of p21.³⁵⁶ In epithelial cells, TGF-β-mediated upregulation of p15 also prevents the non-inhibitory binding of CKI p27 to CDK4. As a result, p15 and p27 turn to bind their own targets which are respectively CDK4 and CDK2 to exert their inhibitory effects.^359,360 Interestingly, in murine B cells, TGF-β increases the expression of p27 instead of p21 to trigger cytostasis,³⁶¹ while in human hematopoietic cells, p57 is likely the only TGF-β-induced CKI for cell cycle arrest.³⁶² Besides CKIs, TGF-β can also target other proliferative factors such as MYC, inhibitors of DNA binding (IDs), and CDC25A to inhibit cell proliferation as mostly shown in epithelial cells. TGF-β induces the transcriptional repression of MYC through a complex containing SMADs, transcription factors E2F4/5 and C/EBPβ, as well as transcriptional corepressor p107.^356,363,364 It also inhibits ID1 expression through SMADs which mediate the induction and recruitment of transcriptional repressor activating transcription factor 3 (ATF3) to target ID1 promoter.³⁶⁵ As for ID2 which can be induced by MYC at the transcriptional level, its suppression by TGF-β is attributed to the downregulation of MYC or the upregulation of antagonistic MYC repressors known as MYC-associated factor X (MAX) dimerization proteins (MADs).^366,367 By these means, TGF-β is able to relieve the transcriptional repression on CKIs exerted by MYC and IDs to facilitate the induction of cytostasis.^{368,369,370,371} Furthermore, TGF-β can downregulate the activity of the CDK-activating phosphatase CDC25A through several mechanisms such as the transcriptional repression by E2F4-p130-HDAC1 complex,³⁷² the inhibitory phosphorylation by RHOA/ROCK1 signaling,³⁷³ as well as the SMAD3-dependent degradative ubiquitination by E3 ubiquitin ligase complex SCF.³⁷⁴ Notably, TGF-β can also stimulate the proliferation of certain cell types, including SMCs, fibroblasts, and chondrocytes, likely due to the induction of autocrine growth factors such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF).^324,325,375
细胞增殖通常由 CDK 通过一系列统称为细胞周期的事件驱动。对于大多数细胞来说，TGF-β 会抑制其增殖，或者换句话说，通过诱导细胞周期停滞在间隙 1 (G1) 期来触发细胞停滞。在上皮细胞和神经胶质细胞中，TGF-β 通过激活 CDK 抑制剂 (CKI)（如 p15 和 p21）的转录来抑制 CDK 的活性，从而诱导细胞停滞。 ^{352 , 353 , 354 , 355} CKI 响应 TGF-β 的转录激活可能是由 SMAD 与转录因子 FOXO ^{355 , 356}或特异性蛋白 1 (SP1) 协同介导的。 ^{357 , 358}值得注意的是，SMAD-FOXO 复合物还需要转录因子 C/EBPβ 来诱导 p15，但不需要诱导 p21。 ³⁵⁶在上皮细胞中，TGF-β 介导的 p15 上调也会阻止 CKI p27 与 CDK4 的非抑制性结合。结果，p15和p27转而结合各自的靶标CDK4和CDK2来发挥抑制作用。 ^{359 , 360}有趣的是，在鼠 B 细胞中，TGF-β 增加 p27 而不是 p21 的表达来触发细胞停滞， ³⁶¹而在人类造血细胞中，p57 可能是唯一 TGF-β 诱导的细胞周期停滞 CKI。 ³⁶²除 CKI 外，TGF-β 还可以靶向其他增殖因子，例如 MYC、DNA 结合抑制剂 (ID) 和 CDC25A，以抑制细胞增殖，这主要在上皮细胞中表现出来。 TGF-β 通过包含 SMAD、转录因子 E2F4/5 和 C/EBPβ 以及转录辅阻遏物 p107 的复合物诱导 MYC 的转录抑制。 ^{356 , 363 , 364}它还通过 SMAD 抑制 ID1 表达，SMAD 介导转录抑制因子激活转录因子 3 (ATF3) 的诱导和募集以靶向 ID1 启动子。 ³⁶⁵至于可由 MYC 在转录水平诱导的 ID2，其被 TGF-β 抑制的原因是 MYC 的下调或称为 MYC 相关因子 X (MAX) 二聚化蛋白 (MAD) 的拮抗 MYC 阻遏物的上调。 ^{366 , 367}通过这些方式，TGF-β 能够解除 MYC 和 ID 对 CKI 的转录抑制，从而促进细胞抑制的诱导。 ^{368、369、370、371此外， TGF} -β 可以通过多种机制下调 CDK 激活磷酸酶 CDC25A 的活性，例如 E2F4-p130-HDAC1 复合物的转录抑制， ³⁷² RHOA/ROCK1 信号传导的抑制性磷酸化， ³⁷³以及 E3 泛素连接酶复合体 SCF 的 SMAD3 依赖性降解泛素化。 ³⁷⁴值得注意的是，TGF-β 还可以刺激某些细胞类型的增殖，包括 SMC、成纤维细胞和软骨细胞，这可能是由于诱导了自分泌生长因子，如成纤维细胞生长因子 (FGF) 和血小板衍生生长因子 (PDGF) 。^{324 , 325 , 375}

As for cell death, TGF-β can trigger apoptosis which is one of the most common forms of cell death in a wide range of cell types including lymphocytes, hepatocytes, podocytes, glial cells, hematopoietic cells, and epithelial cells. Such effect is generally attributed to SMAD-dependent regulation of B-cell lymphoma-2 (BCL-2) family members. More specifically, TGF-β can upregulate pro-apoptotic BCL-2 family members such as BCL-2-associated X protein (BAX) and BCL-2-interacting mediator of cell death (BIM),^{376,377,378,379} meanwhile, it can also downregulate anti-apoptotic BCL-2 family members such as BCL-2 and BCL-extra-large (BCL-XL).^378,380,381 Apart from BCL-2 family members, many other effectors and pathways are also involved in TGF-β-induced cell apoptosis. A septin-like protein known as apoptosis-related protein in the TGF-β signaling pathway (ARTS) undergoes mitochondrial-to-nuclear translocation to promote cell apoptosis in response to TGF-β.³⁸² Death domain-associated protein (DAXX) interacts with TβRII as an intermediary to convey pro-apoptotic TGF-β signal to downstream machinery.³⁸³ In B cells and hepatocytes, TGF-β triggers the transient activation of TAK1/IKK/NF-κB pathway, sequentially leading to the transcriptional activation of IκB-α, the post-repression of NF-κB, the upregulation of JNK signaling, the increase of activator protein 1 (AP-1) complex activity, and finally, the apoptotic death of cells.^384,385,386 In hepatocytes, TGF-β also promotes the expression of growth arrest and DNA damage-inducible β (GADD45β), which functions as a positive mediator of cell apoptosis by acting upstream of p38 MAPK.³⁸⁷ As for podocytes, TGF-β can activate both pro-apoptotic p38 signaling and anti-apoptotic PI3K/AKT signaling to regulate their survival and death.^379,388 In fact, AKT, especially when phosphorylated, can bind to unphosphorylated SMAD3 to inhibit its activity and thus protect several cell types from SMAD-dependent apoptosis. In contrast, TGF-β can prevent the AKT-SMAD3 interaction by triggering SMAD3 phosphorylation to facilitate the cell death program.^389,390 Moreover, in hematopoietic cells, SMAD-dependent TGF-β signaling induces the expression of a central regulator of phospholipid metabolism known as SRC homology 2 (SH2) domain-containing inositol 5’-phosphatase (SHIP) to inhibit AKT phosphorylation as well as cell survival.³⁹¹ Furthermore, TGF-β triggers the apoptosis of oligodendrocytes and epithelial cells by inducing transcription factors TGF-β-inducible early genes (TIEGs) to downregulate BCL-XL expression.^392,393,394 Notably, TGF-β is also found to promote cell survival in certain cases.^{300,395,396,397,398} Related mechanisms involve the AKT-dependent inhibition of FOXO3 as in epithelial cells,³⁹⁹ the suppression of AKT and the induction of BCL-2 as in pre-B lymphocytes,⁴⁰⁰ the early induction and phosphorylation of c-Jun and consequential attenuation of JNK as in lung carcinoma cells,⁴⁰¹ the downregulation of CD95L and p53 as well as the upregulation of NF-κB, BCL-XL, and p21 as in HSCs.⁴⁰²
至于细胞死亡，TGF-β可以引发细胞凋亡，这是多种细胞类型中最常见的细胞死亡形式之一，包括淋巴细胞、肝细胞、足细胞、神经胶质细胞、造血细胞和上皮细胞。这种效应通常归因于 B 细胞淋巴瘤 2 (BCL-2) 家族成员的 SMAD 依赖性调节。更具体地说，TGF-β 可以同时上调促凋亡 BCL-2 家族成员，例如 BCL-2 相关 X 蛋白 (BAX) 和 BCL-2 相互作用细胞死亡介质 ( ^{BIM ) ， 376、377、378、379} ，它还可以下调抗凋亡 BCL-2 家族成员，如 BCL-2 和 BCL-extra-large (BCL-XL)。 ^{378 , 380 , 381}除 BCL-2 家族成员外，许多其他效应子和途径也参与 TGF-β 诱导的细胞凋亡。 TGF-β 信号通路 (ARTS) 中的一种类似脓毒症的蛋白，称为凋亡相关蛋白，会经历线粒体到核的易位，以响应 TGF-β 促进细胞凋亡。 ³⁸²死亡结构域相关蛋白 (DAXX) 作为中介与 TβRII 相互作用，将促凋亡 TGF-β 信号传递至下游机制。 ³⁸³在 B 细胞和肝细胞中，TGF-β 触发 TAK1/IKK/NF-κB 通路瞬时激活，依次导致 IκB-α 转录激活、NF-κB 后抑制、JNK 信号传导上调，激活蛋白 1 (AP-1) 复合物活性增加，最后导致细胞凋亡。^{384 , 385 , 386}在肝细胞中，TGF-β 还促进生长停滞和 DNA 损伤诱导型 β (GADD45β) 的表达，后者通过作用于 p38 MAPK 的上游，充当细胞凋亡的正介体。 ³⁸⁷对于足细胞，TGF-β 可以激活促凋亡 p38 信号传导和抗凋亡 PI3K/AKT 信号传导，以调节其生存和死亡。 ^{379 , 388}事实上，AKT，尤其是磷酸化时，可以与未磷酸化的 SMAD3 结合，抑制其活性，从而保护多种细胞类型免受 SMAD 依赖性细胞凋亡。相反，TGF-β 可以通过触发 SMAD3 磷酸化来阻止 AKT-SMAD3 相互作用，从而促进细胞死亡程序。 ^{389 , 390}此外，在造血细胞中，SMAD 依赖性 TGF-β 信号转导诱导磷脂代谢中央调节因子（称为 SRC 同源 2 (SH2) 结构域）的表达，其中含有肌醇 5'-磷酸酶 (SHIP)，以抑制 AKT 磷酸化，如以及细胞的存活率。 ³⁹¹此外，TGF-β 通过诱导转录因子 TGF-β 诱导早期基因 (TIEG) 下调 BCL-XL 表达，从而引发少突胶质细胞和上皮细胞凋亡。 ^{392 , 393 , 394}值得注意的是，TGF-β 还被发现在某些情况下可以促进细胞存活。^{300、395、396、397、398相关机制涉及上皮}细胞中 FOXO3 的 AKT 依赖性抑制、 ³⁹⁹ AKT 抑制和前 B 淋巴细胞中 BCL-2 的诱导、 ⁴⁰⁰早期诱导和磷酸化c-Jun 和随之而来的 JNK 减弱（如肺癌细胞中）， ⁴⁰¹ CD95L 和 p53 下调以及 NF-κB、BCL-XL 和 p21（如 HSC 中）上调。^第402章

Immune homeostasis 免疫稳态

Generally, TGF-β functions to suppress the activity of multiple immunocompetent cells while inducing the phenotypes of several immune immunosuppressive cells. For this reason, it is regarded as one of the most potent immunosuppressive cytokines which are of vital importance to the maintenance of immune homeostasis and self-immune tolerance.⁴⁰³
一般来说，TGF-β的作用是抑制多种免疫活性细胞的活性，同时诱导多种免疫免疫抑制细胞的表型。因此，它被认为是最有效的免疫抑制细胞因子之一，对于维持免疫稳态和自身免疫耐受至关重要。 ⁴⁰³

Cytotoxic T lymphocytes (CTLs), T helper type 1 (Th1), and Th2 cells
细胞毒性 T 淋巴细胞 (CTL)、1 型辅助 T (Th1) 和 Th2 细胞

TGF-β prevents naïve T cells from differentiating into classical effecter T cells through numerous mechanisms. For CD8+ T cells which can develop into CTLs upon activation, TGF-β inhibits their functions by suppressing the expression of cytolytic factors such as perforin, granzyme A, granzyme B, Fas ligand, and interferon (IFN)-γ. Mechanically, the encoding genes of granzyme B and IFN-γ are directly recognized by SMADs and transcription factor ATF1 which both bind to the gene promoter regions to mediate transcriptional repression in response to TGF-β signaling.⁴⁰⁴ The suppression of IFN-γ release is also correlated to the reduction of transcription factor T-box expressed in T cells (T-BET)⁴⁰⁵ while the decrease in Fas ligand expression is partially attributed to the downregulation of MYC.⁴⁰⁶ In CD4+ T cells, TGF-β inhibits the phosphorylation of T-cell kinase (ITK) to decrease the influx of calcium ion and subsequent activation of nuclear factor of activated T cells (NFATC) which are both critical events for Th1 and Th2 cell differentiation.⁴⁰⁷ TGF-β also suppresses the expression of transcription factors T-BET and GATA-3 in CD4+ T cells which act as master transcriptional activators during Th1 and Th2 cell development respectively.^408,409,410
TGF-β 通过多种机制阻止幼稚 T 细胞分化为经典效应 T 细胞。对于激活后可发育为 CTL 的 CD8+ T 细胞，TGF-β 通过抑制穿孔素、颗粒酶 A、颗粒酶 B、Fas 配体和干扰素 (IFN)-γ 等溶细胞因子的表达来抑制其功能。从机制上讲，颗粒酶 B 和 IFN-γ 的编码基因直接被 SMAD 和转录因子 ATF1 识别，它们都与基因启动子区域结合，介导响应 TGF-β 信号传导的转录抑制。 ⁴⁰⁴ IFN-γ 释放的抑制也与 T 细胞中表达的转录因子 T-box (T-BET) 的减少相关^。405而 Fas 配体表达的减少部分归因于 MYC 的下调。 ⁴⁰⁶在 CD4+ T 细胞中，TGF-β 抑制 T 细胞激酶 (ITK) 的磷酸化，以减少钙离子的流入以及随后激活的 T 细胞核因子 (NFATC) 的激活，这对于 Th1 和 Th2 细胞来说都是关键事件差异化。 ⁴⁰⁷ TGF-β 还抑制 CD4+ T 细胞中转录因子 T-BET 和 GATA-3 的表达，这些转录因子分别在 Th1 和 Th2 细胞发育过程中充当主转录激活剂。 ^{408 , 409 , 410}

Tregs, Th9, and Th17 cells
Tregs、Th9 和 Th17 细胞

TGF-β induces the expression of transcription factor forkhead box P3 (FOXP3) in an interleukin (IL)-2-dependent manner in CD4+ CD25− naïve T cells to convert them into CD4+ CD25+ Tregs which can express TGF-β and inhibit other T cell proliferation with potent immunosuppressive activity.^{411,412,413,414} Similarly, TGF-β can induce the generation of Tregs from CD8+ T cells through the expression of FOXP3.^415,416 Interestingly, IL-4 inhibits the induction of FOXP3 by TGF-β in naïve CD4+ T cells, instead, both cytokines cooperate to drive the differentiation of another Th cell subset known as Th9 cells by inducing the expression of transcription factor purine-rich box-1 (PU.1).^417,418,419 Unlike the immunosuppressive Tregs, these IL-9- and IL-10-secreting cells can potently promote tissue inflammation.^{417,418,419,420} In addition, inflammatory cytokines such as IL-1β, IL-6, IL-21, and IL-23 also suppress TGF-β-induced FOXP3 in naïve CD4+ T cells, meanwhile, they elevate the activity of a TGF-β-induced transcription factor known as retinoic acid receptor-related orphan receptor γt (RORγt) to contribute to the generation of Th17 cells. This pro-inflammatory Th cell subset characterized by IL-17 expression plays important roles in anti-microbial defense and autoimmunity.^421,422
TGF-β 在 CD4+ CD25− 幼稚 T 细胞中以白细胞介素 (IL)-2 依赖性方式诱导转录因子叉头框 P3 (FOXP3) 的表达，将其转化为 CD4+ CD25+ Tregs，后者可以表达 TGF-β 并抑制其他 T 细胞细胞增殖，具有有效的免疫抑制活性。 ^{411、412、413、414类似地，} TGF-β 可以通过 FOXP3 的表达诱导 CD8+ T 细胞产生 Tregs。 ^{415 , 416}有趣的是，IL-4 抑制幼稚 CD4+ T 细胞中 TGF-β 对 FOXP3 的诱导，相反，两种细胞因子通过诱导转录因子嘌呤的表达，协同驱动另一个 Th 细胞亚群（称为 Th9 细胞）的分化丰富的盒子-1 (PU.1)。 ^{417 , 418 , 419}与免疫抑制性 Tregs 不同，这些 IL-9 和 IL-10 分泌细胞可以有效促进组织炎症。 ^{417 , 418 , 419 , 420}此外，IL-1β、IL-6、IL-21 和 IL-23 等炎性细胞因子也在幼稚 CD4+ T 细胞中抑制 TGF-β 诱导的 FOXP3，同时提高其活性TGF-β 诱导的转录因子（称为视黄酸受体相关孤儿受体 γt (RORγt)）有助于 Th17 细胞的生成。这种以 IL-17 表达为特征的促炎 Th 细胞亚群在抗微生物防御和自身免疫中发挥着重要作用。 ^{421 , 422}

B cells B细胞

As critical effectors of humoral immune responses, B cells mainly function by secreting antibodies which are also known as immunoglobulins (Igs). TGF-β decreases B cell Ig secretion by inhibiting the synthesis and the switch from the membrane form to the secreted form of Ig messenger ribonucleic acids (mRNAs).⁴²³ More specifically, TGF-β selectively inhibits the expression of Ig λ light chains while inducing less pronounced reductions in Ig κ light chains,^423,424 moreover, it suppresses the production of isotypes IgM and IgG but enhances the class switching to isotype IgA.^423,425,426 Notably, TGF-β-induced IgA with poor specificity is considered insufficient to mediate immune responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).^427,428 Furthermore, TGF-β can convert B cells into regulatory B cells (Bregs) which produce numerous factors such as TGF-β, IL-10, IL-35, Fas-L, and programmed death-ligand 1 (PD-L1) to mediate immunosuppression.^{429,430,431,432}
作为体液免疫反应的关键效应器，B 细胞主要通过分泌抗体（也称为免疫球蛋白 (Igs)）发挥作用。 TGF-β 通过抑制 Ig 信使核糖核酸 (mRNA) 的合成和从膜形式到分泌形式的转换来减少 B 细胞 Ig 分泌。^{第 423}更具体地说，TGF-β 选择性抑制 Ig λ 轻链的表达，同时诱导 Ig κ 轻链不太明显的减少，^{第 423 ,第 424 章}此外，它抑制同种型 IgM 和 IgG 的产生，但增强向同种型 IgA 的类别转换。 ^{423 , 425 , 426}值得注意的是，特异性较差的 TGF-β 诱导的 IgA 被认为不足以介导抗体依赖性细胞毒性 (ADCC) 和抗体依赖性细胞吞噬作用 (ADCP) 等免疫反应。 ^{427 , 428}此外，TGF-β 可以将 B 细胞转化为调节性 B 细胞 (Breg)，从而产生多种因子，例如 TGF-β、IL-10、IL-35、Fas-L 和程序性死亡配体 1 (PD- L1) 介导免疫抑制。 ^{429、430、431、432​​​}

Natural killer (NK) cells
自然杀伤 (NK) 细胞

NK cells are cytotoxic lymphocytes of the innate immunity. TGF-β suppresses NK cell development by downregulating transcription factor E4 promoter-binding protein 4 (E4BP4) in a SMAD3-dependent manner.⁴³³ The SMAD3 also decreases NK cell IFN-γ secretion through the inhibition of E4BP4 and T-BET.^433,434 Moreover, TGF-β downregulates the surface expression of NK triggering receptors such as NKP30 and NK group 2 member D (NKG2D) which are responsible for the recognition and killing of target cells.^435,436 It also negatively regulates the expression of cytolytic factors such as granzyme A, granzyme B, and perforin through SMAD signaling to further impair NK cytotoxicity.^434,436
NK 细胞是先天免疫的细胞毒性淋巴细胞。 TGF-β 通过以 SMAD3 依赖性方式下调转录因子 E4 启动子结合蛋白 4 (E4BP4) 来抑制 NK 细胞发育。 ⁴³³ SMAD3 还通过抑制 E4BP4 和 T-BET 减少 NK 细胞 IFN-γ 分泌。 ^{433 , 434}此外，TGF-β 下调 NK 触发受体的表面表达，例如负责识别和杀死靶细胞的 NKP30 和 NK 2 组成员 D (NKG2D)。 ^{435 , 436}它还通过 SMAD 信号传导负调节细胞溶解因子（例如颗粒酶 A、颗粒酶 B 和穿孔素）的表达，以进一步削弱 NK 细胞毒性。 ^{434 , 436}

DCs, macrophages, and neutrophils
DC、巨噬细胞和中性粒细胞

DCs, macrophages, and neutrophils can function as antigen-presenting cells (APCs), which are the keys to the activation of adaptive immune responses. TGF-β can impair antigen presentation through the downregulation of major histocompatibility complex (MHC) molecules.^437,438,439 It also reduces the expression of IL-12 and co-stimulatory molecules such as CD40 in macrophages and CD80, CD83, and CD86 in DCs to interfere in APC-mediated immune cell activation.^440,441 Apart from antigen presentation, TGF-β also inhibits the cytotoxicity of macrophages, on one hand, through the downregulation of cytotoxic factors, such as TNF-α and nitric oxide (NO),^{442,443,444,445,446} on the other hand, by suppressing the activity of Fcγ receptors (FcγRs) which function to mediate the ADCC and ADCP of macrophages.⁴⁴⁷ Moreover, TGF-β can trigger the polarization of macrophages and neutrophils from classical M1 macrophages and N1 neutrophils to alternative M2 macrophages and N2 neutrophils which are characterized by multiple immunosuppressive properties.^{439,448,449,450}
DC、巨噬细胞和中性粒细胞可以充当抗原呈递细胞（APC），是激活适应性免疫反应的关键。 TGF-β 可以通过下调主要组织相容性复合体 (MHC) 分子来损害抗原呈递。 ^{437 , 438 , 439}它还降低 IL-12 和共刺激分子（例如巨噬细胞中的 CD40 和 DC 中的 CD80、CD83 和 CD86 ）的表达，以干扰 APC 介导的免疫细胞激活。 ^{440 , 441}除了抗原呈递之外，TGF-β 一方面还通过下调细胞毒性因子，如 TNF-α 和一氧化氮 (NO) 来抑制巨噬细胞的细胞毒性， ^{442 , 443 , 444 , 445 , 446}另一方面，通过抑制 Fcγ 受体 (FcγR) 的活性，FcγR 的功能是介导巨噬细胞的 ADCC 和 ADCP。 ⁴⁴⁷此外，TGF-β 可以触发巨噬细胞和中性粒细胞从经典 M1 巨噬细胞和 N1 中性粒细胞极化为具有多种免疫抑制特性的替代 M2 巨噬细胞和 N2 中性粒细胞。 ^{439、448、449、450​​​}

Dysfunctional TGF-β signaling can play key roles in numerous pathological processes, contributing to the disorders of developmental defects, aberrant healing, fibrotic diseases, inflammatory diseases, infectious diseases, as well as tumors (Fig. 6).
功能失调的TGF-β信号传导可在许多病理过程中发挥关键作用，导致发育缺陷、异常愈合、纤维化疾病、炎症性疾病、传染病以及肿瘤等疾病（图6 ）。

TGF-β signaling in disease. Dysfunctional TGF-β signaling is involved in numerous pathological processes. a Mutations that lead to decreased or increased TGF-β signaling can cause various developmental defects. b Deficient TGF-β signaling contributes to wound chronicity while excess TGF-β signaling leads to wound scarring and tissue fibrosis by stimulating ECM deposition through fibroblast activation and EMT/EndMT. c Dysfunctional TGF-β signaling exacerbates tissue injuries in inflammatory diseases and infectious diseases by promoting inflammation, pathogen infection, and tissue remodeling. d Aberrant TGF-β signaling is implicated in all aspects of tumor development including tumorigenesis, tumor growth, tumor invasion, tumor metastasis, as well as tumor microenvironment (TME) remodeling. (CTGF, connective tissue growth factor; IFN-γ, interferon-γ; IL-6, interleukin-6; solid arrows from TGF-β indicate excessive TGF-β signaling, dashed arrows from TGF-β indicate deficient TGF-β signaling)
疾病中的 TGF-β 信号传导。功能失调的 TGF-β 信号传导参与许多病理过程。 a导致 TGF-β 信号传导减少或增加的突变可能导致各种发育缺陷。 b TGF-β 信号传导不足会导致伤口慢性化，而过多的 TGF-β 信号传导则通过成纤维细胞激活和 EMT/EndMT 刺激 ECM 沉积，导致伤口疤痕和组织纤维化。 c功能失调的 TGF-β 信号传导通过促进炎症、病原体感染和组织重塑，加剧炎症性疾病和传染病中的组织损伤。 d异常的 TGF-β 信号传导涉及肿瘤发展的各个方面，包括肿瘤发生、肿瘤生长、肿瘤侵袭、肿瘤转移以及肿瘤微环境 (TME) 重塑。 （CTGF，结缔组织生长因子；IFN-γ，干扰素-γ；IL-6，白介素-6；TGF-β 的实线箭头表示 TGF-β 信号传导过多，TGF-β 的虚线箭头表示 TGF-β 信号传导不足）

Full size image

Developmental defects 发育缺陷

Loss of TβRI or TβRII functions due to homozygous mutations generally results in embryonic lethality in mice due to defects in the hematopoiesis and vasculogenesis of yolk sac.^451,452 However, the lack of different TGF-β isoforms can lead to distinct phenotypes in mice, consistent with the isoform-specific roles of TGF-β in embryonic development. TGF-β1-knockout mice show no gross developmental abnormalities in spite of the defective hematopoiesis and vasculogenesis in yolk sac during embryonic development.^452,453,454 In contrast, TGF-β2-knockout mice exhibit perinatal mortality and a wide range of developmental defects in heart, lungs, bones, eyes, inner ears, craniofacial structures, urogenital organs, and hair follicles.^{290,455,456,457,458} TGF-β3-knockout mice also die shortly after birth but show no detectable abnormalities except for cleft palate and abnormal lung development.^459,460 Notably, palatal shelves that fail to elevate in TGF-β2-knockout mice undergo elevation in TGF-β3-knockout mice but still fail in fusion.^455,459,460 Also, branching morphogenesis and respiratory epithelial cell differentiation which appear normal in the lungs of TGF-β2-knockout mice are defective in TGF-β3-knockout mice.^455,459 In humans, loss-of-function mutations of a single TGF-β signaling component such as TGF-β2,^461,462,463 TGF-β3,^464,465,466 TβRI,^467,468,469 TβRII,^470,471,472 SMAD2,^473,474,475 or SMAD3^476,477,478 can cause Loeys-Dietz syndrome (LDS), an autosomal dominant connective tissue disorder with a range of cardiovascular, skeletal, craniofacial, and cutaneous manifestations. LDS patients typically present with features including congenital heart defects, aneurysms, arterial tortuosity and dissections, skeletal overgrowth, cervical spine instability, clubfoot deformity, craniosynostosis, hypertelorism, bifid uvula, cleft palate, thin skin, and mental retardation. Dermal fibroblasts derived from LDS patients demonstrate impaired deposition of extracellular collagen and elastin, suggesting a possible mechanism of the connective tissue defects of the patients.^479,480 However, the aortic tissues of LDS patients show increased accumulation of collagen, elevated expression of connective tissue growth factor (CTGF), and enhanced activity of non-mutant TGF-β signaling components.^{461,462,463,465,467,468,475,476,481,482} Therefore, primary downregulation and compensatory upregulation of TGF-β signaling are both responsible for the abnormalities of LDS.
由于纯合突变而导致的 TβRI 或 TβRII 功能丧失通常会因卵黄囊的造血和血管生成缺陷而导致小鼠胚胎死亡。 ^{451 , 452}然而，缺乏不同的 TGF-β 同工型可导致小鼠出现不同的表型，这与 TGF-β 在胚胎发育中的同工型特异性作用一致。尽管胚胎发育过程中卵黄囊的造血和血管生成存在缺陷，但 TGF-β1 敲除小鼠并未表现出明显的发育异常。 ^{452、453、454相反，} TGF-β2 敲除小鼠表现出围产期死亡率以及心脏、肺、骨骼、眼睛、内耳、颅面结构、泌尿生殖器官和毛囊的广泛发育缺陷。 ^{290 , 455 , 456 , 457 , 458} TGF-β3 敲除小鼠也在出生后不久死亡，但除了腭裂和肺部发育异常外，没有显示出可检测到的异常。 ^{459 , 460}值得注意的是，在 TGF-β2 敲除小鼠中未能升高的腭架在 TGF-β3 敲除小鼠中经历升高，但仍然无法融合。 ^{455 , 459 , 460}此外，在 TGF-β2 敲除小鼠的肺部中表现正常的分支形态发生和呼吸道上皮细胞分化在 TGF-β3 敲除小鼠中却存在缺陷。^{455 , 459}在人类中，单一 TGF-β 信号成分的功能丧失突变，例如^{TGF - β2、461、462、463} TGF- ^{β3、464、465、466 TβRI 、 467、468、469 TβRII 、 470 、 471、472 SMAD2、473、474、475或SMAD3 476、477、478可引起}Loeys-Dietz 综合征（LDS），一种常染色体显性结缔组织疾病，具有一系列心血管、骨骼、颅面和皮肤表现。 LDS 患者的典型特征包括先天性心脏缺陷、动脉瘤、动脉迂曲和夹层、骨骼过度生长、颈椎不稳定、马蹄内翻足畸形、颅缝早闭、距离过远、悬雍垂裂、腭裂、皮肤薄和智力低下。来自 LDS 患者的真皮成纤维细胞表现出细胞外胶原蛋白和弹性蛋白沉积受损，这表明患者结缔组织缺陷的可能机制。 ^{479 , 480}然而，LDS 患者的主动脉组织表现出胶原蛋白积累增加、结缔组织生长因子 (CTGF) 表达升高以及非突变 TGF-β 信号成分活性增强。^{461 , 462 , 463 , 465 , 467 , 468 , 475 , 476 , 481 , 482}因此，TGF-β信号的原发性下调和代偿性上调均是LDS异常的原因。

Excessive TGF-β signaling can also act as a primary pathogenic factor in developmental defects. In mice, overexpression of TGF-β or SMAD can lead to developmental abnormalities in several tissues, such as skin,^483,484 bones,⁴⁸⁵ eyes,⁴⁸⁶ lungs,^487,488 mammary glands,^489,490,491 salivary glands,⁴⁹² and central nervous system.⁴⁹³ In humans, Camurati-Engelmann disease (CED), a progressive bone dysplasia inherited in an autosomal dominant manner, is ascribed to mutations of TGF-β1, which lead to increased TGF-β1 activation and signaling.^494,495 This disease is characterized by hyperostosis and sclerosis of the long bones and the skull.^496,497 Studies on CED have suggested that hyperactive TGF-β1 in the bone microenvironment can induce osteoclasts and osteoblasts to increase but cluster in separated areas, uncoupling bone resorption and formation to cause bone remodeling defects.^494,498,499
过度的 TGF-β 信号传导也可能是发育缺陷的主要致病因素。在小鼠中，TGF-β 或 SMAD 的过度表达可导致多种组织发育异常，例如皮肤^{、 483、484}骨骼、 ⁴⁸⁵眼睛、 ⁴⁸⁶肺^{、 487、488}乳腺^{、 489、490、491唾液腺}、 ⁴⁹²和中枢神经系统。 ⁴⁹³在人类中，卡穆拉蒂-恩格尔曼病 (CED) 是一种以常染色体显性遗传方式遗传的进行性骨发育不良，归因于 TGF-β1 突变，导致 TGF-β1 激活和信号转导增加。 ^{494 , 495}这种疾病的特点是长骨和颅骨骨质增生和硬化。 ^{496 , 497} CED 研究表明，骨微环境中过度活跃的 TGF-β1 可诱导破骨细胞和成骨细胞增加，但聚集在不同的区域，使骨吸收和形成脱钩，导致骨重塑缺陷。 ^{494 , 498 , 499}

Aberrant healing and fibrotic diseases
异常愈合和纤维化疾病

Dysregulated TGF-β signaling can contribute to the tissue damage in aberrant healing and fibrotic diseases which are caused by all kinds of injuries such as wounding, burns, radiation, infection, and inflammation.
TGF-β信号传导失调可导致异常愈合和纤维化疾病中的组织损伤，这些损伤是由各种损伤（如受伤、烧伤、辐射、感染和炎症）引起的。

Aberrant healing 异常愈合

The lack of TGF-β and TβR expression is commonly found in the chronic wounds in patients, indicating that deficient TGF-β signaling may lead to wound chronicity and even unhealing.^{500,501,502,503,504,505} However, in vivo studies in mice have reported quite complicated findings. An activating mutation of TβRI can lead to a regenerative healing phenotype which enables rapid regeneration of normal tissues with differentiated structures instead of scar formation in ear punch wounds.⁵⁰⁶ Paradoxically, overexpression of TGF-β1 in keratinocytes accelerates the re-epithelialization in partial-thickness cutaneous wounds but slows that of full-thickness cutaneous wounds.^507,508 In TGF-β1-deficient mice, the healing of full-thickness cutaneous wounds is initially normal but ultimately damaged by severe inflammatory diseases.⁵⁰⁹ In immunodeficient mice without inflammatory diseases, the lack of TGF-β1 still leads to significant delays in each healing stage of full-thickness cutaneous wounds.⁵¹⁰ However, loss of TGF-β signaling in keratinocytes due to expression of dominant negative TβRII leads to increased proliferation and reduced apoptosis, thus facilitating the re-epithelialization in full-thickness cutaneous wounds.⁵¹¹ Furthermore, cutaneous wound healing is accelerated in mice lacking SMAD3 but is aberrant in mice lacking SMAD4 exclusively in keratinocytes.^512,513
患者的慢性伤口中普遍存在TGF-β和TβR表达缺失，表明TGF-β信号传导缺陷可能导致伤口慢性化甚至不愈合。 ^{500、501、502、503、504、505然而，小鼠体内研究}报告了相当复杂的发现。 TβRI 的激活突变可导致再生愈合表型，使具有分化结构的正常组织能够快速再生，而不是在耳部穿孔伤口中形成疤痕。 ⁵⁰⁶矛盾的是，角质形成细胞中 TGF-β1 的过度表达会加速部分皮层皮肤伤口的再上皮化，但会减慢全层皮肤伤口的再上皮化。 ^{507 , 508}在 TGF-β1 缺陷小鼠中，全层皮肤伤口的愈合最初是正常的，但最终会受到严重炎症性疾病的损害。 ⁵⁰⁹在没有炎症性疾病的免疫缺陷小鼠中，TGF-β1 的缺乏仍然会导致全层皮肤伤口的每个愈合阶段显着延迟。 ⁵¹⁰然而，由于显性失活 TβRII 的表达，角质形成细胞中 TGF-β 信号传导丧失，导致增殖增加和细胞凋亡减少，从而促进全层皮肤伤口的上皮化。 ⁵¹¹此外，在缺乏 SMAD3 的小鼠中，皮肤伤口愈合加速，但在角质形成细胞中完全缺乏 SMAD4 的小鼠中，皮肤伤口愈合却异常。 ^{512 , 513}

In contrast to chronic wounds, hypertrophic scars and keloids both characterized by overabundant ECM deposition are the results of hyperactive cutaneous wound healing. In fact, the expression of TGF-β and TβR which decreases eventually in normal cutaneous wounds remains elevated in hypertrophic scars and keloids.^{514,515,516,517,518} In contrast to normal cutaneous fibroblasts, both keloid fibroblasts and hypertrophic scar fibroblasts are significantly higher in collagen production, however, only keloid fibroblasts exhibit increased sensitivity to TGF-β stimulation.⁵¹⁹ For keloid fibroblasts, overexpressed TGF-β can promote the resistance to apoptosis, the ability of proliferation, the conversion to MFs, and the expression of CTGF and VEGF, thus contributing to the ECM deposition, focal adhesion, fibrous growth, and angiogenesis in keloid tissues.^{518,520,521,522,523}
与慢性伤口相反，肥厚性疤痕和疤痕疙瘩均以过量的 ECM 沉积为特征，是皮肤伤口愈合过度活跃的结果。事实上，在正常皮肤伤口中最终降低的 TGF-β 和 TβR 表达在肥厚性疤痕和疤痕疙瘩中仍然升高。 ^{514、515、516、517、518与正常皮肤成}纤维细胞相比，疤痕疙瘩成纤维细胞和肥厚性疤痕成纤维细胞的胶原蛋白生成显着较高，然而，只有疤痕疙瘩成纤维细胞表现出对 TGF-β 刺激的敏感性增加。 ⁵¹⁹对于瘢痕疙瘩成纤维细胞来说，过表达的 TGF-β 可促进其抗凋亡、增殖能力、向 MF 的转化以及 CTGF 和 VEGF 的表达，从而促进 ECM 沉积、粘斑、纤维生长和血管生成。疤痕组织。 ^{518、520、521、522、523​​​​}

Fibrotic diseases 纤维化疾病

Besides wounding, other forms of injurious stimulation can also cause excessive ECM deposition in different kinds of tissues, leading to fibrotic diseases, which are closely associated with the hyperactivity of TGF-β signaling.
除创伤外，其他形式的伤害性刺激也会导致不同组织中ECM过度沉积，导致纤维化疾病，这与TGF-β信号传导的过度活跃密切相关。

TGF-β expression is significantly elevated in fibrotic lungs in various cases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF).^{524,525,526,527,528} In situ hybridization and immunohistochemical staining suggest that alveolar macrophages and epithelial cells are likely the major sources of TGF-β which contribute to the fibrosis of lungs.^526,527,528 In vitro studies show that TGF-β1 can trigger the EMT of alveolar epithelial cells and enhance the activity of lung fibroblasts to mediate fibrogenic effects.^{529,530,531,532} Transgenic expression of TGF-β1 in murine and rat lungs induces pulmonary fibrosis which is accompanied by alveolar EMT, MF differentiation, and mononuclear-rich inflammation.^{532,533,534,535} Interestingly, the suppression of TGF-β1, the deletion of TβRII, the ablation of SMAD3, the upregulation of SMAD7, but the administration of TGF-β3 can all significantly protect mice from experimentally induced pulmonary fibrosis.^{535,536,537,538,539}
在各种情况下，例如特发性肺纤维化（IPF）和囊性纤维化（CF），TGF-β表达在纤维化肺中显着升高。 ^{524、525、526、527、528原位杂交和免疫}组织化学染色表明，肺泡巨噬细胞和上皮细胞可能是导致肺纤维化的 TGF-β 的主要来源。 ^{526 , 527 , 528}体外研究表明TGF-β1可以触发肺泡上皮细胞的EMT并增强肺成纤维细胞的活性以介导纤维化作用。 ^{529 , 530 , 531 , 532}小鼠和大鼠肺中 TGF-β1 的转基因表达会诱导肺纤维化，并伴有肺泡 EMT、MF 分化和富含单核细胞的炎症。 ^{532、533、534、535有趣的是}，TGF-β1 的抑制、TβRII 的缺失、SMAD3 的消除、SMAD7 的上调，但 TGF-β3 的施用都可以显着保护小鼠免受实验诱导的肺纤维化。 ^{535、536、537、538、539​​​​}

Similarly, the fibrotic kidneys of human glomerulonephritis, IgA nephropathy, diabetic nephropathy, lupus nephritis, as well as renal allografts in chronic rejection all show significant increases in three TGF-β isoforms in the glomeruli and tubulointerstitium where ECM deposition and PAI-1 production is closely related to the expression of TGF-β1 isoform in particular.^{540,541,542,543} In vitro, TGF-β1 stimulates kidney fibroblasts, mesangial cells, glomerular epithelial cells, and tubular epithelial cells to produce several ECM components and remodelers such as collagen, fibronectin, laminin, proteoglycan, MMP, and TIMP.^{544,545,546,547,548,549,550} TGF-β1 also contributes to the EMT induction and MF differentiation in renal fibrosis.⁵⁵⁰ Transgenic mice that have increased levels of TGF-β1 in plasma develop progressive renal disease characterized by glomerulosclerosis and tubulointerstitial fibrosis with TIMP overexpression and ECM deposition in sub-endothelial and mesangial locations.^551,552
同样，人类肾小球肾炎、IgA 肾病、糖尿病肾病、狼疮性肾炎的纤维化肾脏以及慢性排斥反应中的肾同种异体移植物都显示出肾小球和肾小管间质中三种 TGF-β 同工型的显着增加，其中 ECM 沉积和 PAI-1 的产生是尤其与TGF-β1亚型的表达密切相关。 ^{540、541、542、543在体外，} TGF-β1 刺激肾成纤维细胞、系膜细胞、肾小球上皮细胞和肾小管上皮细胞产生多种 ECM 成分和重塑剂，例如胶原、纤连蛋白、层粘连蛋白、蛋白聚糖、MMP 和 TIMP。 ^{544 , 545 , 546 , 547 , 548 , 549 , 550} TGF-β1 也有助于肾纤维化中的 EMT 诱导和 MF 分化。 ⁵⁵⁰只血浆中 TGF-β1 水平升高的转基因小鼠出现进行性肾病，其特征是肾小球硬化和肾小管间质纤维化，伴有 TIMP 过度表达和 ECM 在内皮下和系膜位置沉积。 ^551、552​

In fibrotic livers, TGF-β1 expression increases markedly with fibrogenic activity.^{553,554,555,556} Induction of TGF-β1 expression in murine livers leads to hepatic fibrosis characterized by prominent ECM deposition in peri-sinusoidal areas with activation of HSCs and apoptosis of hepatocytes.^557,558 Notably, activated HSCs which play a major role in hepatic fibrosis can provide an important source of TGF-β,⁵⁵⁹ while overproduced TGF-β can in turn activate several signaling pathways such as those of SMAD, MEK, JNK, PI3K, and JAK/STAT in HSCs to contribute to their functions.^236,237
在纤维化肝脏中，TGF-β1 表达随着纤维化活性显着增加。 ^{553 , 554 , 555 , 556}在小鼠肝脏中诱导 TGF-β1 表达会导致肝纤维化，其特征是在肝窦周围区域出现显着的 ECM 沉积，并伴有 HSC 激活和肝细胞凋亡。第^{557章、第558章}HSC 中的 JAK/STAT 有助于发挥其功能。 ^{236 , 237}

As for the cardiovascular system, TGF-β is also elevated during myocardial fibrosis, valve fibrosis, and arteriosclerosis, generally attributed to the expression by SMCs, fibroblasts, endothelial cells, and inflammatory cells such as macrophages.^{560,561,562,563,564,565,566,567,568,569} On one hand, TGF-β can stimulate cardiovascular fibroblasts to differentiate into MFs and produce ECM components and remodelers,^{562,563,570,571,572,573} on the other hand, it can also stimulate endothelial cells to undergo EndMT to induce their fibrogenic phenotype.^569,574,575
对于心血管系统，TGF-β在心肌纤维化、瓣膜纤维化和动脉硬化期间也会升高，通常归因于平滑肌细胞、成纤维细胞、内皮细胞和巨噬细胞等炎症细胞的表达。 ^{560 , 561 , 562 , 563 , 564 , 565 , 566 , 567 , 568 , 569}一方面，TGF-β可以刺激心血管成纤维细胞分化为MF并产生ECM成分和重塑剂， ^{562 , 563 , 570 , 571 , 572 , 573}另一方面，它还可以刺激内皮细胞进行 EndMT，诱导其纤维化表型。 ^{569、574、575​​}

Furthermore, TGF-β is widely involved in the fibrosis of many other tissues and diseases as in the cases of cutaneous fibrosis,^576,577 muscular fibrosis,⁵⁷⁸ pancreatic fibrosis,^{579,580,581,582} myelofibrosis,^583,584 adenomyosis,⁵⁸⁵ autoimmune diseases,^{238,527,573,586,587,588,589} and infectious diseases.^{590,591,592,593}
此外，TGF-β 广泛参与许多其他组织和疾病的纤维化，如皮肤纤维化^{、 576、577}肌肉纤维化、 ⁵⁷⁸胰腺纤维化^{、 579、580、581、582骨髓纤维化、 583、584}子宫腺肌病、 ⁵⁸⁵自身^{免疫性疾病、 238、527、573、586、587、588、589和传染病。 590、591、592、593​​​}

Inflammatory diseases and infectious diseases
炎症性疾病和传染病

Inflammatory diseases and infectious diseases can demonstrate aberrant immune responses and various tissue injuries which usually implicate the dysfunction of TGF-β signaling.
炎症性疾病和传染病可以表现出异常的免疫反应和各种组织损伤，这通常与 TGF-β 信号传导功能障碍有关。

Inflammatory diseases 炎症性疾病

Since TGF-β acts as a negative regulator to maintain immune homeostasis, deficient TGF-β signaling can lead to hyperactive immune responses, contributing to the pathology of numerous inflammatory diseases. TGF-β1-null mice initially appear normal after birth but soon develop a rapid wasting syndrome accompanied by a multifocal inflammatory disease which leads to organ failure and early death by 3-4 weeks of age.^{453,594,595,596} Many organs in these mice, including heart, lungs, stomach, liver, pancreas, and muscles, all exhibit massive infiltration of inflammatory cells such as lymphocytes, macrophages, and granulocytes. Moreover, their total numbers of blood leukocytes increase mainly due to the elevated absolute numbers of neutrophils and monocytes, while their levels of autoantibodies, MHC molecules, and inflammatory cytokines such as IFN-γ, TNF-α, and CCL3 also rise correspondingly in serum or tissues.
由于 TGF-β 作为维持免疫稳态的负调节因子，TGF-β 信号传导缺陷会导致免疫反应过度活跃，从而导致多种炎症性疾病的病理。 TGF-β1缺失的小鼠出生后最初表现正常，但很快就会出现快速消耗综合征，并伴有多灶性炎症性疾病，导致器官衰竭并在3-4周龄时过早死亡。 ^{453 , 594 , 595 , 596}这些小鼠的许多器官，包括心脏、肺、胃、肝脏、胰腺和肌肉，都表现出淋巴细胞、巨噬细胞和粒细胞等炎症细胞的大量浸润。此外，其血液白细胞总数增加主要是由于中性粒细胞和单核细胞绝对数升高，而血清中自身抗体、MHC分子以及IFN-γ、TNF-α、CCL3等炎性细胞因子的水平也相应升高或纸巾。

In the absence of any pathogens, the inflammatory diseases in TGF-β1-knockout mice actually resemble a special group of inflammatory diseases known as autoimmune diseases, which are characterized by dysregulated immune responses attacking self-tissues. In fact, even cell type-specific loss of TGF-β signaling can lead to the development of various autoimmune diseases in mice.^{597,598,599,600,601,602,603,604} In patients with autoimmune diseases such as systemic lupus erythematosus (SLE),^605,606,607 systemic sclerosis (SSc),^{608,609,610,611} rheumatoid arthritis (RA),^612,613,614 Sjögren’s syndrome,^{586,614,615,616} Crohn’s disease,^{587,617,618,619} ulcerative colitis (UC),^{617,618,619,620,621,622} autoimmune hepatitis (AIH),^623,624 and Hashimoto’s thyroiditis (HT),^606,625,626 the levels of TGF-β or TβR in tissues or circulation are associated with the presence, activity, and severity of the diseases. Notably, although all these diseases show correlations with dysregulated TGF-β signaling, their correlations with TGF-β levels can be either positive or negative. Some cases of the diseases are likely caused by insufficient TGF-β expression and thus exhibit decreased TGF-β production.^{619,622,627,628,629,630} In other cases, however, the autoimmune inflammation is likely attributed to impaired cell responsiveness to TGF-β especially due to deficient TβR functions, therefore, TGF-β production is elevated as a compensatory response.^{624,628,631,632,633,634,635}
在没有任何病原体的情况下，TGF-β1敲除小鼠的炎症性疾病实际上类似于一组特殊的炎症性疾病，称为自身免疫性疾病，其特征是攻击自身组织的免疫反应失调。事实上，即使细胞类型特异性的 TGF-β 信号传导丧失也可能导致小鼠患上各种自身免疫性疾病。 ^{597 , 598 , 599 , 600 , 601 , 602 , 603 , 604}患有自身免疫性疾病的患者，例如系统性红斑狼疮（SLE）， ^{605 , 606 , 607}系统性硬化症（SSc）， ^{608 , 609 , 610 , 611}类风湿性关节炎（ RA) ^{、 612、613、614干燥综合征、 586、614、615、616克罗恩}病^{、 587、617、618、619溃疡性结肠炎( UC ) 、 617、618、619、620、621、622小鼠}肝炎 (AIH) 、 ^{623 、 624}和桥本甲状腺炎(HT) ^{606 、 625 、 626}组织或循环中TGF-β 或TβR 的水平与疾病的存在、活动性和严重程度相关。值得注意的是，尽管所有这些疾病都与 TGF-β 信号传导失调相关，但它们与 TGF-β 水平的相关性可以是正相关，也可以是负相关。 某些疾病病例可能是由 TGF-β 表达不足引起的，因此表现出 TGF-β 产生减少。 ^{619 , 622 , 627 , 628 , 629 , 630}然而，在其他情况下，自身免疫性炎症可能归因于细胞对 TGF-β 的反应性受损，特别是由于 TβR 功能缺陷，因此，作为补偿反应，TGF-β 的产生升高。^{624、628、631、632、633、634、635​​​​​​}

Allergic diseases, including asthma, allergic rhinitis, food allergy, and atopic dermatitis, are another group of inflammatory diseases that are caused by aberrant immune responses to harmless environmental antigens. TGF-β production is increased in the airways and serum of asthmatic patients and is further increased after allergen exposure, disease progression, or certain treatments.^{636,637,638,639,640,641,642,643,644,645,646} Bronchial epithelial cells, fibroblasts, SMCs, eosinophils, neutrophils, and macrophages can all contribute to the excessive TGF-β production in asthmatic patients.^{641,642,643,644,645,646,647,648,649,650} However, the functions of TGF-β are seemingly contradictory in the context of allergic airway inflammation, for TGF-β can either enhance or suppress the activity of eosinophils, lymphocytes, macrophages, and mast cells in asthma.^{648,651,652,653,654,655,656,657,658,659,660,661} Nevertheless, it is clear that TGF-β can promote asthmatic airway remodeling by inducing airway EMT,^662,663 ECM production,^649,650 MF differentiation,^664,665 and smooth muscle hyperplasia.⁶⁴⁷ In patients with allergic rhinitis, TGF-β levels in serum are found dependent on allergen exposure, while TGF-β and TβR expression in nasal mucosa is noticed correlated with intra-epithelial mast cell abundance.^666,667,668 In fact, allergen challenge can activate TGF-β signaling in the mast cells and epithelial cells in nasal mucosa which may contribute to the mast cell accumulation and goblet cell hyperplasia in allergic rhinitis.^669,670 Allergen challenge can also induce the loss of TGF-β1-expressing Bregs and Tregs which function to suppress the inflammatory Th2 responses of allergic rhinitis. However, with prolonged challenging time, the proportion of TGF-β1-expressing Bregs and Tregs can gradually recover to reconstitute the immune homeostasis in nasal mucosa.⁶⁷¹ Similarly, TGF-β can inhibit the Th2 responses of food allergy by promoting Treg activity in the intestines.^603,672,673 Therefore, reduced TGF-β1 expression in the intestinal epithelial cells and mononuclear cells of patients with food allergy can partially account for the development of the disease.^603,674 Moreover, TGF-β can inhibit the pathology of atopic dermatitis by suppressing B cell maturation, mast cell activation, eosinophil infiltration, as well as the secretion of IgE, TNF-α, and histamine by those cells.^675,676,677 Aberrant TGF-β expression or attenuated cell responsiveness discovered in patients with atopic dermatitis may play a key role in the disorder.^678,679,680
过敏性疾病，包括哮喘、过敏性鼻炎、食物过敏和特应性皮炎，是另一类由对无害环境抗原的异常免疫反应引起的炎症性疾病。哮喘患者气道和血清中 TGF-β 的产生增加，并且在接触过敏原、疾病进展或某些治疗后进一步增加。 ^{636 , 637 , 638 , 639 , 640 , 641 , 642 , 643 , 644 , 645 , 646}支气管上皮细胞、成纤维细胞、SMC、嗜酸性粒细胞、中性粒细胞和巨噬细胞均可导致哮喘患者产生过多的 TGF-β。 ^{641 , 642 , 643 , 644 , 645 , 646 , 647 , 648 , 649 , 650}然而，TGF-β 的功能在过敏性气道炎症中似乎是矛盾的，因为 TGF-β 可以增强或抑制 TGF-β 的活性。哮喘中的嗜酸性粒细胞、淋巴细胞、巨噬细胞和肥大细胞。 ^{648 , 651 , 652 , 653 , 654 , 655 , 656 , 657 , 658 , 659 , 660 , 661}然而，很明显 TGF-β 可以通过诱导气道 EMT 来促进哮喘气道重塑， ^{662 , 663} ECM 产生， ^{649 ,第650章}MF分化，^{第664章，第665章和}平滑肌增生。⁶⁴⁷在过敏性鼻炎患者中，血清中的 TGF-β 水平取决于过敏原暴露，而鼻粘膜中的 TGF-β 和 TβR 表达与上皮内肥大细胞丰度相关。 ^{666 , 667 , 668}事实上，过敏原攻击可以激活鼻粘膜肥大细胞和上皮细胞中的 TGF-β 信号传导，这可能有助于过敏性鼻炎中肥大细胞的积累和杯状细胞增生。 ^{669 , 670}过敏原攻击还可以诱导表达 TGF-β1 的 Breg 和 Tregs 的丧失，这些 Breg 和 Tregs 的功能是抑制过敏性鼻炎的炎症 Th2 反应。然而，随着攻击时间的延长，表达TGF-β1的Bregs和Tregs的比例可以逐渐恢复，从而重建鼻粘膜的免疫稳态。 ⁶⁷¹同样，TGF-β 可以通过促进肠道中的 Treg 活性来抑制食物过敏的 Th2 反应。 ^{603 , 672 , 673}因此，食物过敏患者肠上皮细胞和单核细胞中 TGF-β1 表达的减少可以部分解释该疾病的发展。 ^{603 , 674}此外，TGF-β 可以通过抑制 B 细胞成熟、肥大细胞活化、嗜酸性粒细胞浸润以及这些细胞分泌 IgE、TNF-α 和组胺来抑制特应性皮炎的病理。 ^{675 , 676 , 677}在特应性皮炎患者中发现的异常 TGF-β 表达或减弱的细胞反应性可能在该疾病中发挥关键作用。^{678 , 679 , 680}

Furthermore, TGF-β signaling is implicated in the pathology of other inflammatory diseases and inflammation-related diseases such as bronchitis,⁶⁴² pancreatitis,^681,682,683 glomerulonephritis,^684,685 osteomyelitis,⁶⁸⁶ arthritis,⁶⁸⁷ diabetes,⁶⁸⁸ and Alzheimer’s disease (AD).^{689,690
第642章}胰腺炎，^{第681章，第682章，第683章}肾小球肾炎，^{第684章，第685章685}骨髓炎，^第686章关节炎，^第687章糖尿病，^第688章和阿尔茨海默病（第642章）广告）。 ^{689 , 690}

Infectious diseases 传染病

Infectious diseases caused by different kinds of pathogenic organisms can result in tissue damage due to diverse pathogen virulence and dysregulated host responses.
由不同种类的病原生物引起的传染病可由于不同的病原体毒力和宿主反应失调而导致组织损伤。

TGF-β can function to reduce pathogen burdens as well as tissue injuries in some cases of infection. In patients with H1N1 influenza A virus sepsis, blood TGF-β levels are negatively correlated with clinical severity scores on admission.⁶⁹¹ Consistently, increased TGF-β activity in mice confers resistance against lethal influenza infection due to reductions in both viral titers and pulmonary inflammation.^692,693 TGF-β expression also prevents mice from coxsackievirus-induced myocarditis and type 1 diabetes in a Treg-dependent manner.^694,695 Moreover, TGF-β acts as a pro-survival factor to protect murine neurons and intestinal epithelial cells against cell death during reovirus infection.^696,697 As for bacterial infection, TGF-β can attenuate sepsis-induced tissue injuries through mechanisms involving the induction of Tregs.⁶⁹⁸ It also enhances the pathogen clearance and host resistance of mice during the infection of Streptococcus pneumoniae,⁶⁹⁹ Streptococcus pyogenes,⁷⁰⁰ Listeria monocytogenes,⁷⁰¹ and Yersinia enterocolitica,⁷⁰² likely, by suppressing IFN-γ, TNF-α, and IL-6 production while promoting Th17 and Treg responses. In rats with pulmonary cryptococcosis, TGF-β reduces fungal burdens by promoting the lysozyme secretion of macrophages, meanwhile, it also limits inflammation by inhibiting macrophage phagocytosis, chemokine production, and oxidative burst.⁷⁰³ Moreover, TGF-β can be protective during parasitic infection. The lack of TGF-β exacerbates the severity of murine malaria infection, whereas TGF-β treatment, in contrast, suppresses plasmodium proliferation and prolongs mice survival with decreased TNF-α and increased IL-10 in serum.⁷⁰⁴ During Trypanosoma congolense infection, exogenous TGF-β1 confers early protection against parasitemia, anemia, splenomegaly, and mortality due to enhanced macrophage activity and Th1 responses which are characterized by increased NO, IFN-γ, TNF-α, IL-12, and IgG2a production.⁷⁰⁵ During Toxoplasma infection, TGF-β can prevent tissue damage by reducing inflammatory cell infiltration and cytokine production, while it can also improve the outcomes of infection-related abnormal pregnancy by promoting Treg functions and suppressing NK cytotoxicity.^{706,707,708,709} Furthermore, TGF-β can prevent the lung injuries during hookworm infection by inducing the immunosuppressive activity of myeloid cells to reduce Th2 responses.⁷¹⁰
TGF-β 可以减少病原体负担以及某些感染病例中的组织损伤。在患有 H1N1 甲型流感病毒脓毒症的患者中，血液 TGF-β 水平与入院时的临床严重程度评分呈负相关。 ⁶⁹¹一致地，由于病毒滴度和肺部炎症的减少，小鼠体内 TGF-β 活性的增加赋予了对致命性流感感染的抵抗力。 ^{692 , 693} TGF-β 表达还以 Treg 依赖性方式预防小鼠柯萨奇病毒诱导的心肌炎和 1 型糖尿病。 ^{694 , 695}此外，TGF-β 作为一种促生存因子，可保护小鼠神经元和肠上皮细胞在呼肠孤病毒感染期间免遭细胞死亡。 ^{696 , 697}对于细菌感染，TGF-β 可以通过诱导 Tregs 的机制减轻脓毒症引起的组织损伤。^第698章还可以通过抑制IFN-γ、TNF-α和IL-6的产生，增强小鼠感染肺炎链球菌、化脓性链球菌、700单核细胞^{增生李斯特}菌、 ⁷⁰¹和小肠结肠炎耶尔森菌、 ⁷⁰²可能的病原体清除率和宿主抵抗力同时促进 Th17 和 Treg 反应。在患有肺隐球菌病的大鼠中，TGF-β通过促进巨噬细胞溶菌酶的分泌来减轻真菌负荷，同时还通过抑制巨噬细胞的吞噬作用、趋化因子的产生和氧化爆发来限制炎症。⁷⁰³此外，TGF-β 在寄生虫感染期间可以发挥保护作用。 TGF-β 的缺乏会加剧小鼠疟疾感染的严重性，而 TGF-β 治疗则相反，可抑制疟原虫增殖并延长小鼠的存活时间，同时血清中的 TNF-α 减少，IL-10 增加。 ⁷⁰⁴在刚果锥虫感染期间，外源性 TGF-β1 可提供早期保护，防止寄生虫血症、贫血、脾肿大和死亡，因为巨噬细胞活性和 Th1 反应增强，其特点是 NO、IFN-γ、TNF-α、IL-12 和IgG2a 的产生。 ⁷⁰⁵在弓形虫感染期间，TGF-β 可以通过减少炎症细胞浸润和细胞因子产生来预防组织损伤，同时还可以通过促进 Treg 功能和抑制 NK 细胞毒性来改善感染相关的异常妊娠的结局。 ^{706 , 707 , 708 , 709}此外，TGF-β 可以通过诱导骨髓细胞的免疫抑制活性来减少 Th2 反应，从而预防钩虫感染期间的肺损伤。⁷¹⁰

In other cases of infection, however, TGF-β can turn to facilitate pathogen infection and tissue injuries. In clinical patients, circulating TGF-β1 levels are positively correlated with the severity and mortality of severe community-acquired pneumonia (CAP)⁷¹¹ and sepsis-induced acute respiratory distress syndrome (ARDS).⁷¹² Increased TGF-β production can impair the anti-bacterial functions of neutrophils, uncouple the cytokine production and glycolysis of macrophages, and suppress the IL-2 expression and proliferation of T cells to participate in the pathology of sepsis.^713,714,715 As for bacterial infection in local tissues, on one hand, TGF-β can upregulate fibronectin and integrins in hosts to promote bacterial adhesion and invasion,^716,717 on the other hand, it can attenuate anti-infectious innate responses and Th1 responses while inducing immunotolerant Treg responses to facilitate the immune escape of the pathogens.^{718,719,720,721,722} TGF-β-mediated immunosuppression can also contribute to viral infection, as elevated TGF-β expression during viral infection not only impairs early innate immunity such as IFN responses, NK functions, and macrophage activity but also suppresses the adaptive immune responses of T cells and B cells.^{428,723,724,725,726,727,728,729,730,731} Notably, TGF-β can also enhance viral infection through certain pathogen-specific mechanisms as in the cases of human immunodeficiency virus type 1 (HIV-1) infection,^732,733,734 human T-cell leukemia virus type I (HTLV-I) infection,⁷³⁵ hepatitis C virus (HCV) infection,⁷³⁶ Zika virus (ZIKV) infection,⁷³⁷ as well as rubella virus (RuV) infection.⁷³⁸ Furthermore, TGF-β can promote the survival and growth of parasites in hosts through downregulation of NO, IFN-γ, TNF-α, IL-6, IL-17, and Th17 cells as well as upregulation of IL-4, IL-10, and Treg cells, contributing to the infection of Fasciola hepatica,⁷³⁹ Echinococcus multilocularis,⁷⁴⁰ Toxoplasma gondii,⁷⁴¹ Leishmania,⁷⁴² and Plasmodium.^743,744
然而，在其他感染情况下，TGF-β 可能会促进病原体感染和组织损伤。在临床患者中，循环TGF-β1水平与严重社区获得性肺炎（CAP） ⁷¹¹和脓毒症引起的急性呼吸窘迫综合征（ARDS）的严重程度和死亡率呈正相关。 ⁷¹² TGF-β 产生增加可损害中性粒细胞的抗菌功能，解开巨噬细胞的细胞因子产生和糖酵解作用，并抑制 T 细胞的 IL-2 表达和增殖，从而参与脓毒症的病理。 ^{713 , 714 , 715}对于局部组织的细菌感染，TGF-β一方面可以上调宿主体内的纤连蛋白和整合素，促进细菌粘附和侵袭， ^{716 , 717}另一方面，可以减弱抗感染的先天反应和 Th1 反应，同时诱导免疫耐受的 Treg 反应，以促进病原体的免疫逃逸。 ^{718 , 719 , 720 , 721 , 722} TGF-β 介导的免疫抑制也可能导致病毒感染，因为病毒感染期间 TGF-β 表达升高不仅损害早期先天免疫，如 IFN 反应、NK 功能和巨噬细胞活性，而且抑制 T 细胞和 B 细胞的适应性免疫反应。^{428 , 723 , 724 , 725 , 726 , 727 , 728 , 729 , 730 , 731}值得注意的是，TGF-β 还可以通过某些病原体特异性机制增强病毒感染，例如人类免疫缺陷病毒 1 型 (HIV-1)^{第732章733 、第734章}人类T细胞白血病病毒I型（HTLV-I）感染、^第735章丙型肝炎病毒（HCV）感染、^第736章寨卡病毒（ZIKV）感染、^第737章以及风疹病毒（RuV）感染。 ⁷³⁸此外，TGF-β 可以通过下调 NO、IFN-γ、TNF-α、IL-6、IL-17 和 Th17 细胞以及上调 IL-4、IL，促进宿主体内寄生虫的存活和生长。^第739章多房棘球绦虫，^第740章弓形虫，^第741章利什曼原虫，^第742章和疟原虫。^{743 , 744}

Tumors 肿瘤

It is generally accepted that TGF-β acts as a tumor suppressor during the early stages of tumorigenesis but turns into a tumor promotor at later stages of tumor development.
人们普遍认为，TGF-β在肿瘤发生的早期阶段充当肿瘤抑制因子，但在肿瘤发展的后期变成肿瘤促进因子。

Tumorigenesis 肿瘤发生

Evidence from animal models firmly establishes the suppressor role of TGF-β signaling in early tumorigenesis. TGF-β and its receptors can be strongly induced in the murine epidermis upon exposure to carcinogens that tend to disrupt tissue homeostasis and cause oncogenic transformation.^745,746 Increased TGF-β expression in murine epidermis can potently attenuate cell proliferation and confer resistance to hyperproliferation induced by carcinogens.^316,746,747 Similarly, in murine mammary epithelia, the overexpression of TGF-β or TβR can result in remarkable protection from carcinogen-induced tumorigenesis with reduced premalignant lesions, prolonged tumor latency, and decreased cancer incidence.^{25,491,748,749,750} Such tumor-inhibitory effects by TGF-β signaling are attributed to the early apoptosis of differentiating cells and, more importantly, the premature senescence of stem cells which reduces the reproductive capacity of the mammary epithelia and thus decreases the frequency with which transforming mutations may occur and be fixed in the cell population.^491,748
来自动物模型的证据明确证实了 TGF-β 信号传导在早期肿瘤发生中的抑制作用。当小鼠接触致癌物质时，TGF-β及其受体会在小鼠表皮中被强烈诱导，从而破坏组织稳态并导致致癌转化。 ^{745 , 746}小鼠表皮中 TGF-β 表达的增加可以有效减弱细胞增殖并赋予对致癌物诱导的过度增殖的抵抗力。 ^{316 , 746 , 747}同样，在小鼠乳腺上皮中，TGF-β 或 TβR 的过度表达可以显着防止致癌物诱导的肿瘤发生，减少癌前病变，延长肿瘤潜伏期，并降低癌症发病率。 ^{25 , 491 , 748 , 749 , 750} TGF-β 信号传导的这种肿瘤抑制作用归因于分化细胞的早期凋亡，更重要的是干细胞的过早衰老，从而降低了乳腺上皮的生殖能力，从而降低细胞群中可能发生并固定的转化突变的频率。 ^{491 , 748}

In contrast, loss of TGF-β signaling can be an early event that contributes to tumorigenesis. In clinical patients, heterogeneous patterns of TβRII expression in normal breast lobular units as well as loss of TβRII expression in breast epithelial hyperplastic lesions are both associated with increased risks of invasive breast cancer.⁷⁵¹ More convincing evidence is provided by germline mutations of TGF-β signaling components which show strong correlations with increased risks of tumorigenesis. Loss-of-function TβRI mutations can result in an autosomal dominant skin cancer condition known as multiple self-healing squamous epithelioma (MSSE) or Ferguson-Smith disease (FSD) which is characterized by multiple squamous-carcinoma-like skin tumors that invade locally and then regress spontaneously after several months.^752,753 Inactivating TβRII mutations are considered causative of some cases of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, an autosomal dominant cancer predisposition syndrome, by impairing cell growth inhibition in response to TGF-β.⁷⁵⁴ Moreover, germline mutations of SMAD4 are responsible for juvenile polyposis, an autosomal dominant syndrome predisposing to gastrointestinal hamartomatous polyps and cancers.^755,756 Mechanically, impaired TGF-β signaling can cause serious disturbance to tissue homeostasis, thus largely facilitating the development of pre-neoplastic lesions, as well as subsequent tumors, as shown in different murine tissues with deficiencies in the activity of TGF-β,^757,758 TβR,^{749,759,760,761,762,763,764,765,766,767,768,769,770} or SMAD.^{657,771,772,773,774,775,776} Among them, TβR-deleted murine epithelia exhibit significant reductions in p15 and p21 and remarkable increases in MYC expression and RAS/ERK signaling, accompanied by elevated cell proliferation, reduced cell apoptosis, and enhanced cell malignant transformation to become tumorigenic.^{762,763,764,765}
相反，TGF-β信号传导的丧失可能是导致肿瘤发生的早期事件。在临床患者中，正常乳腺小叶单位中 TβRII 表达的异质性以及乳腺上皮增生性病变中 TβRII 表达的缺失均与浸润性乳腺癌风险增加相关。 ⁷⁵¹ TGF-β 信号成分的种系突变提供了更有说服力的证据，这些突变与肿瘤发生风险增加密切相关。功能丧失的 TβRI 突变可导致常染色体显性皮肤癌，称为多发性自愈性鳞状上皮瘤 (MSSE) 或弗格森-史密斯病 (FSD)，其特征是局部侵袭的多发性鳞状癌样皮肤肿瘤然后几个月后自然消退。 ^{752 , 753} TβRII 失活突变被认为是某些遗传性非息肉病性结直肠癌 (HNPCC) 或 Lynch 综合征（一种常染色体显性癌症易感综合征）病例的病因，其原因是损害对 TGF-β 的细胞生长抑制。 ⁷⁵⁴此外，SMAD4 的种系突变导致幼年性息肉病，这是一种易患胃肠道错构瘤性息肉和癌症的常染色体显性综合征。^{755 , 756}从机制上讲，受损的 TGF-β 信号传导可导致组织稳态严重紊乱，从而在很大程度上促进肿瘤前病变以及后续肿瘤的发展，如不同 TGF-β 活性缺陷的小鼠组织所示^{、 757、758TβR 、 749、759、760、761、762、763、764、765、766、767、768、769、770或SMAD 。​​​​​​​​ 657 , 771 , 772 , 773 , 774 , 775 , 776}其中，TβR 缺失的小鼠上皮表现出 p15 和 p21 显着减少，MYC 表达和 RAS/ERK 信号显着增加，伴随着细胞增殖增加，细胞凋亡减少，并增强细胞恶性转化以产生致瘤性。^{762 , 763 , 764 , 765}

Furthermore, TGF-β can provide additional protection against tumorigenesis by controlling pathogen infection,⁷⁷⁷ inhibiting excessive inflammation,^{778,779,780,781} reducing genomic instability,⁷⁸² inducing replicative senescence,⁷⁸³ and regulating epithelial-mesenchymal interaction.⁷⁸⁴
此外，TGF-β 可以通过控制病原体感染、 ⁷⁷⁷抑制^{过度炎症、 778、779、780、781}减少基因组不稳定性、 ⁷⁸²诱导复制性衰老、 ⁷⁸³和调节上皮-间质相互作用来提供针对肿瘤发生的额外保护。^第784章

Tumor growth 肿瘤生长

TGF-β can inhibit tumor growth by triggering cytostasis and apoptosis through similar mechanisms as it does in cells from normal tissues. In tumor cells, TGF-β signaling induces cell cycle arrest by targeting effectors, such as p15,^354,356 p21,^355,785,786 p27,³⁶¹ MYC,³⁶³ ID,⁷⁸⁷ and CDC25A,^374,786 while it also induces apoptotic cell death through effectors including CTGF,⁷⁸⁸ programmed cell death 4 (PDCD4),⁷⁸⁹ Fas receptor,⁷⁹⁰ death-associated protein kinase (DAPK),⁷⁹¹ DAXX,³⁸³ IκB-α,^384,386 sex-determining region Y (SRY)-box 4 (SOX4),⁷⁹² ARTS,³⁸² TIEGs,⁷⁹³ as well as several BCL-2 family members.^{794,795,796,797,798,799,800} Consistently, primary tumors induced from murine tissues with intact TGF-β signaling pathways are initially responsive to TGF-β-mediated inhibitory effects.^{491,749,759,764,801,802}
TGF-β 可以通过与正常组织细胞中类似的机制触发细胞停滞和细胞凋亡来抑制肿瘤生长。在肿瘤细胞中，TGF-β信号传导通过靶向效应子（例如^{p15、354、356 p21、355、785、786 p27、361 MYC 、 363} ID、 ⁷⁸⁷和 CDC25A、 ^{374、786 ）}诱导细胞周期停滞^，同时还诱导细胞凋亡^第788章程序性细胞死亡4（PDCD4）、^第789章Fas受体、^第790章死亡相关蛋白激酶（DAPK）、^第791章DAXX、^第383章IκB-α、^{第384章、第386章}box 4 (SOX4)、 ⁷⁹² ARTS、 ³⁸² TIEG、 ⁷⁹³以及几个 BCL-2 家族成员。 ^{794 , 795 , 796 , 797 , 798 , 799 , 800}一致地，由具有完整 TGF-β 信号通路的小鼠组织诱导的原发性肿瘤最初对 TGF-β 介导的抑制作用有反应。 ^{491、749、759、764、801、802​​​​​}

On the contrary, deficient TGF-β signaling can potently promote the growth of tumors. The downregulation of tumor TGF-β signaling in many cases is attributed to reduced expression or inactivating mutations of TβR or SMAD, as shown in various tumor types such as leukemia,⁷⁷² lymphoma,^803,804 esophageal cancer,^805,806,807 gastric cancer,⁸⁰⁸ colorectal cancer,^{30,807,809,810,811} pancreatic cancer,^32,812,813 biliary cancer,⁸¹² ampullary cancer,⁸¹⁴ thyroid cancer,⁸¹⁵ prostate cancer,^816,817 breast cancer,⁸¹⁸ ovarian cancer,⁸¹⁹ endometrial cancer,⁸⁰⁸ genital squamous cell carcinomas (SCC),⁷⁶⁴ head and neck SCC,^{820,821,822,823} etc. These changes are able to confer resistance to the tumor-inhibitory effects of TGF-β. In mouse models, tumors developed from tissues with deletion or inactivation of TβR exhibit increased cell proliferation and decreased cell apoptosis, accompanied by reduction in p15, p21, and p27, the elevation of MYC, cyclin D1, and epidermal growth factor receptor (EGFR), as well as activation of STAT3 and PI3K/AKT pathways.^{761,762,763,764,765} Interestingly, reconstituted expression of TβRII in tumor cells with corresponding deficiency not only restores the inhibitory responses to TGF-β but also significantly attenuates the tumorigenicity of these cells.⁸²⁴
相反，TGF-β信号传导缺陷可以有效促进肿瘤的生长。在许多情况下，肿瘤 TGF-β 信号传导的下调归因于 TβR 或 SMAD 的表达减少或失活突变，如多种肿瘤类型所示，如白血病、 ⁷⁷²淋巴瘤、 ^{803 、 804}食管癌、 ^{805 、 806 、 807}胃癌, ⁸⁰⁸结直肠癌, ^{30 , 807 , 809 , 810 , 811}胰腺癌, ^{32 , 812 , 813}胆道癌, ⁸¹²壶腹癌, ⁸¹⁴甲状腺癌, ⁸¹⁵前列腺癌, ^{816 , 817}乳腺癌, ⁸¹⁸卵巢癌, ⁸¹⁹子宫内膜癌, ⁸⁰⁸生殖器鳞状细胞癌 (SCC), ⁷⁶⁴头颈 SCC, ^{820 , 821 , 822 , 823}等。这些变化能够赋予对 TGF-β 肿瘤抑制作用的抵抗力。在小鼠模型中，由 TβR 缺失或失活的组织发展而来的肿瘤表现出细胞增殖增加和细胞凋亡减少，并伴有 p15、p21 和 p27 减少，MYC、细胞周期蛋白 D1 和表皮生长因子受体 (EGFR) 升高以及 STAT3 和 PI3K/AKT 通路的激活。^{761 , 762 , 763 , 764 , 765}有趣的是，在具有相应缺陷的肿瘤细胞中重建 TβRII 表达不仅恢复了对 TGF-β 的抑制反应，而且还显着减弱了这些细胞的致瘤性。^第824章

Notably, TGF-β can fail to suppress the growth of tumors where there is likely no loss of functional TGF-β signaling components, and even formerly inhibited tumor cells can subsequently resume proliferating in vitro and develop larger tumor masses in vivo.^354,825,826 On one hand, such resistance may result from the dysfunction of the downstream targets of TGF-β signaling such as CKIs.³⁵⁴ On the other hand, the tumor-suppressive signaling of TGF-β can be offset or interfered by enhanced I-SMAD activity⁸²⁷ or potent oncogenic factors such as E1A,^828,829 EVI1,^148,830 SKI,^150,152 SNO,¹⁵³ MYC,⁸³¹ ID2,⁸³² mutant p53,⁸³³ as well as RAS/RAF/ERK signaling.^162,834 Moreover, TGF-β-mediated tumor-promoting effects can also account for the enhanced tumor growth in vivo, as discussed in a later section.
值得注意的是，在功能性 TGF-β 信号成分可能没有丧失的情况下，TGF-β 可能无法抑制肿瘤的生长，甚至以前被抑制的肿瘤细胞随后也可以在体外恢复增殖并在体内形成更大的肿瘤块。 ^{354 , 825 , 826}一方面，这种抵抗可能是由于 TGF-β 信号下游靶点（例如 CKI）的功能障碍造成的。 ³⁵⁴另一方面，TGF-β 的肿瘤抑制信号传导可被增强的 I-SMAD 活性抵消或干扰⁸²⁷或强效致癌因子，如 E1A、 ^{828、829 EVI1、148、830 SKI 、 150、152 SNO} 、^第153章MYC，^第831章ID2，^第832章突变体p53，^第833章以及RAS/RAF/ERK信号传导。 ^{162 , 834}此外，TGF-β 介导的肿瘤促进作用也可以解释体内肿瘤生长增强的原因，如后面部分所述。

Tumor invasion and metastasis
肿瘤侵袭和转移

Contrary to its role as a suppressor of tumor growth, TGF-β generally acts as a promoter of tumor invasion and metastasis especially in advanced tumors. Upregulation of TGF-β as well as its receptors is associated with disease progression and poor prognosis in some patients with tumors such as breast cancer,^835,836 pancreatic cancer,^837,838 and gastric cancer.⁸³⁹ Consistently, TGF-β overexpression or pre-treatment enables tumor cells to form increased metastases in vivo,^825,840 while loss of TGF-β responsiveness due to the introduction of dominant negative TβRII decreases the metastatic efficiency of high-grade tumor cells.^841,842 Moreover, tumors derived from transgenic murine epithelia that overexpress TGF-β or TβR are significantly more malignant and more invasive.^{491,749,750,802,843} Notably, these TGF-β-overexpressing tumor cells are more likely to undergo the transition from epithelial cell phenotype into spindle cell phenotype which is the most malignant and invasive cell type.^802,843 This indicates that TGF-β can facilitate the progression of epithelial-derived tumors through the induction of EMT which is inoperative in tumors with deficiencies in TβR or SMAD.^{761,770,774,842,843} Similar to the EMT of normal cells, TGF-β-induced EMT of tumor cells is characterized by changes in keratin, integrin, cadherin, catenin, claudin, vimentin, occludin, fibronectin, and MMP expression which can contribute to the invasive and metastatic capacity of tumors.^{197,198,200,203,230,232,750,774,802,843,844,845,846,847,848}
与其作为肿瘤生长抑制剂的作用相反，TGF-β通常充当肿瘤侵袭和转移的促进者，尤其是在晚期肿瘤中。 TGF-β及其受体的上调与某些肿瘤患者的疾病进展和不良预后相关，例如乳腺癌^{、 835、836}胰腺癌、 ^837、838和胃癌。 ⁸³⁹一致地，TGF-β 过度表达或预处理使肿瘤细胞在体内形成增加的转移， ^825、840而由于显性失活 TβRII 的引入而导致 TGF-β 反应性丧失，从而降低了高级肿瘤细胞的转移效率。 ^{841 , 842}此外，源自过度表达 TGF-β 或 TβR 的转基因鼠上皮的肿瘤明显更恶性且更具侵袭性。 ^{491 , 749 , 750 , 802 , 843}值得注意的是，这些TGF-β过表达的肿瘤细胞更有可能从上皮细胞表型转变为梭形细胞表型，梭形细胞表型是最具恶性和侵袭性的细胞类型。 ^{802 , 843}这表明 TGF-β 可以通过诱导 EMT 来促进上皮源性肿瘤的进展，而 EMT 在 TβR 或 SMAD 缺陷的肿瘤中不起作用。^{761 , 770 , 774 , 842 , 843}与正常细胞的 EMT 类似，TGF-β 诱导的肿瘤细胞 EMT 的特点是角蛋白、整合素、钙粘蛋白、连环蛋白、claudin、vimentin、occludin、纤连蛋白和 MMP 表达的变化这有助于肿瘤的侵袭和转移能力。^{197、198、200、203、230、232、750、774、802、843、844、845、846、847、848​​​​​​​​​​​​​​}

However, loss of functional TGF-β signaling components can occur in tumor cells during disease progression.^759,809 In fact, reduced TGF-β signaling can also contribute to tumor invasion and metastasis. For some patients, decreased expression of TβR is correlated with higher tumor grades, later clinical stages, and worse clinical prognosis.^805,816,818 A large number of cell models and mouse models also demonstrate that tumors lacking TGF-β signaling tend to be more malignant and more aggressive.^{758,760,761,762,764,801,841,843,849,850,851,852} Relevant mechanisms in these cases involve the loss of E-cadherin,⁷⁶¹ the reduction in PAI,⁸⁴⁹ the increase in RHO/RAC signaling,⁸⁴³ the activation of integrin/focal adhesion kinase (FAK)/SRC/MAPK pathway,⁷⁶⁴ and more importantly, the overexpression of various pro-invasive and pro-metastatic factors. In mouse models, deficient TGF-β signaling can stimulate tumor cells and stromal cells to produce high levels of TGF-β and other tumor-promoting factors such as CTGF, VEGF, IL-1β, C-X-C motif chemokine ligand (CXCL8), CXCL12, cyclooxygenase(COX)-2, MMPs, collagen, and tenascin C (TNC) which can strongly promote tumor angiogenesis, fibroblasts activation, immune infiltration, and ECM remodeling.^{760,761,762,763,764,774,843,850}
然而，在疾病进展过程中，肿瘤细胞中可能会出现功能性 TGF-β 信号传导成分的丧失。 ^{759 , 809}事实上，TGF-β 信号传导减少也可能导致肿瘤侵袭和转移。对于某些患者来说，TβR 表达降低与较高的肿瘤分级、较晚的临床分期和较差的临床预后相关。 ^{805 , 816 , 818}大量细胞模型和小鼠模型也证明缺乏TGF-β信号传导的肿瘤往往更恶性且更具侵袭性。 ^{758、760、761、762、764、801、841、843、849、850、851、852这些病例的相关机制涉及E-钙粘蛋白的}丢失、 ⁷⁶¹ PAI 的减少、 ⁸⁴⁹ RHO/RAC 信号传导的增加^第843章整合素/粘着斑激酶（FAK）/SRC/MAPK通路的激活，^第764章更重要的是，各种促侵袭和促转移因子的过度表达。在小鼠模型中，TGF-β信号传导缺陷可以刺激肿瘤细胞和基质细胞产生高水平的TGF-β和其他促肿瘤因子，如CTGF、VEGF、IL-1β、CXC基序趋化因子配体（CXCL8）、CXCL12、环加氧酶（COX）-2、MMP、胶原蛋白和肌腱蛋白C（TNC）能够强烈促进肿瘤血管生成、成纤维细胞活化、免疫浸润和ECM重塑。 ^{760、761、762、763、764、774、843、850​​​​​​​}

Tumor microenvironment (TME) remodeling
肿瘤微环境（TME）重塑

TGF-β can stimulate tumor progression even when its signaling pathways are unavailable in the tumor cells, indicating its additional tumor-promoting effects exerted on tumor stroma.^{760,761,762,763,764,843} Fibroblasts, endothelial cells, and immune cells are the major stromal cell types in TME and can all be manipulated by TGF-β in favor of tumor progression.
即使肿瘤细胞中不存在其信号通路，TGF-β也可以刺激肿瘤进展，这表明它对肿瘤基质具有额外的促肿瘤作用。 ^{760 , 761 , 762 , 763 , 764 , 843}成纤维细胞、内皮细胞和免疫细胞是 TME 中的主要基质细胞类型，都可以被 TGF-β 操纵，有利于肿瘤进展。

Actively produced TGF-β in the TME can stimulate the chemotactic migration of fibroblasts and convert them into MFs which are also known as cancer-associated fibroblasts (CAFs) in terms of tumors.^305,853 Activated CAFs can in turn repay TME with more TGF-β as well as other tumor-promoting factors such as TGF-α, FGF, HGF, PDGF, and CTGF to exert a strong stimulation on tumor growth.^{324,853,854,855,856,857} Moreover, TGF-β regulates the production of various ECM components and remodelers by CAFs to facilitate the migration of tumor cells during invasion and metastasis.^855,858 Interestingly, fibroblasts with the loss of TβRII can also contribute to tumor development through the production of TGF-α, HGF, and macrophage-stimulating protein (MSP).⁸⁵⁹
TME中活跃产生的TGF-β可以刺激成纤维细胞的趋化迁移，并将其转化为MF，在肿瘤方面也称为癌症相关成纤维细胞（CAF）。 ^{305 , 853}激活的CAF反过来可以回报TME更多的TGF-β以及其他促肿瘤因子如TGF-α、FGF、HGF、PDGF和CTGF，对肿瘤生长产生强烈刺激。 ^{324 , 853 , 854 , 855 , 856 , 857}此外，TGF-β 调节 CAF 产生各种 ECM 成分和重塑剂，以促进肿瘤细胞在侵袭和转移过程中的迁移。 ^{855 , 858}有趣的是，TβRII 缺失的成纤维细胞也可以通过产生 TGF-α、HGF 和巨噬细胞刺激蛋白 (MSP) 来促进肿瘤的发展。^第859章

Endothelial cells can also be converted into CAFs through TGF-β-mediated EndMT.⁸⁶⁰ More importantly, TGF-β promotes the angiogenesis of endothelial cells by inducing VEGF production in tumor cells and fibroblasts.^{323,354,750,861,862} TGF-β also disrupts inter-endothelial junctions to increase the vascular permeability in TME through the process of EndMT and the induction of angiopoietin-like 4 (ANGPTL4).⁸⁶³ Therefore, TGF-β-mediated angiogenesis not only increases the blood supply to tumors to favor their growth but also provides tumors with more accessible entrances into the circulation to form metastasis.
内皮细胞也可以通过 TGF-β 介导的 EndMT 转化为 CAF。 ⁸⁶⁰更重要的是，TGF-β 通过诱导肿瘤细胞和成纤维细胞产生 VEGF 来促进内皮细胞的血管生成。 ^{323、354、750、861、862 TGF - β还}通过 EndMT 过程和诱导血管生成素样 4 (ANGPTL4) 破坏内皮间连接，从而增加 TME 中的血管通透性。 ⁸⁶³因此，TGF-β介导的血管生成不仅增加了肿瘤的血液供应以有利于其生长，而且还为肿瘤提供了更容易进入循环的入口以形成转移。

Furthermore, TGF-β can modulate immune cell activity to facilitate tumor survival and development. TGF-β inhibits the tumoricidal activity of macrophages and neutrophils and polarizes them into tumor-promoting M2 macrophages and N2 neutrophils, which are also known as tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) in terms of tumors.^{439,442,444,448,449,864} It also promotes the functions of Tregs while suppressing the cytotoxicity of CTLs and NK cells to facilitate tumor evasion from immune surveillance.^{865,866,867,868,869} Moreover, TGF-β can inhibit the expression of MHC antigens in tumor cells to further attenuate their recognition by adaptive anti-tumor immunity.^870,871 However, TGF-β-mediated downregulation of MHC antigens and NKG2D ligands can increase tumor susceptibility to NK cytotoxicity to some extent.^233,872
此外，TGF-β可以调节免疫细胞活性，促进肿瘤的存活和发展。 TGF-β抑制巨噬细胞和中性粒细胞的杀肿瘤活性，并将其极化为促癌M2巨噬细胞和N2中性粒细胞，在肿瘤方面也称为肿瘤相关巨噬细胞（TAM）和肿瘤相关中性粒细胞（TAN）。 ^{439 , 442 , 444 , 448 , 449 , 864}它还促进Tregs的功能，同时抑制CTL和NK细胞的细胞毒性，以促进肿瘤逃避免疫监视。 ^{865 , 866 , 867 , 868 , 869}此外，TGF-β可以抑制肿瘤细胞中MHC抗原的表达，通过适应性抗肿瘤免疫进一步减弱它们的识别。 ^{870 , 871}然而，TGF-β 介导的 MHC 抗原和 NKG2D 配体的下调可以在一定程度上增加肿瘤对 NK 细胞毒性的敏感性。 ^{233 , 872}

To rectify the dysfunction of TGF-β in different kinds of diseases, several targeted therapies have been developed to regulate TGF-β activity at the levels of biosynthesis, activation, and signaling. Many completed clinical trials have preliminarily confirmed the safety and efficacy of some therapeutic strategies, while there are still numerous clinical trials ongoing at present (Table 1).
为了纠正不同类型疾病中 TGF-β 的功能障碍，已经开发了几种靶向疗法来在生物合成、激活和信号传导水平上调节 TGF-β 活性。许多已完成的临床试验已初步证实了一些治疗策略的安全性和有效性，同时仍有大量临床试验正在进行中（表1 ）。

Alteration of TGF-β biosynthesis
TGF-β生物合成的改变

Targeting TGF-β mRNAs 靶向 TGF-β mRNA

Trabedersen (AP 12009 or OT-101) is an antisense oligonucleotide complementary to human TGF-β2 mRNA and can specifically inhibit TGF-β2 biosynthesis. It is hypothesized that trabedersen mainly acts by reversing TGF-β2-mediated immunosuppression to facilitate immune responses against tumors. A phase 2b clinical trial showed no advantage in early tumor control rate but in long-term survival rate for glioma patients treated with trabedersen in comparison with standard chemotherapy. Tumor responses which continued to increase long after discontinuation in the study suggested that the clinically relevant beneficial effects of trabedersen might increase over time. Moreover, compared with the standard chemotherapy group, drug-related or possibly drug-related adverse events in the trabedersen group were less common and mostly nervous system disorders. The study also indicated that the optimal dose of trabedersen is 10 µM, as both its efficacy and safety tended to be superior to the 80 µM dose, although the mechanism for this counterintuitive result has not been fully understood.⁸⁷³ TGF-β1 antisense oligonucleotides or small interfering RNAs (siRNAs) were also developed and evaluated in different pre-clinical models, suggested as potential therapeutic strategies for tuberculosis,^874,875 wound scarring,^876,877 and several renal diseases.^{878,879,880,881}
Trabedersen（AP 12009 或 OT-101）是一种与人 TGF-β2 mRNA 互补的反义寡核苷酸，可以特异性抑制 TGF-β2 生物合成。据推测，trabedersen 主要通过逆转 TGF-β2 介导的免疫抑制来促进针对肿瘤的免疫反应。一项 2b 期临床试验显示，与标准化疗相比，接受 Trabedersen 治疗的神经胶质瘤患者在早期肿瘤控制率方面没有优势，但在长期生存率方面没有优势。研究中止后很长时间内肿瘤反应持续增加，这表明 Trabedersen 的临床相关有益效果可能会随着时间的推移而增加。而且，与标准化疗组相比，trabedersen组中药物相关或可能与药物相关的不良事件较少见，且多为神经系统疾病。研究还表明，trabedersen 的最佳剂量是 10 µM，因为其功效和安全性往往优于 80 µM 剂量，尽管这种违反直觉的结果的机制尚未完全了解。 [第^{873章]第874章878、879、880、881​​​}

TGF-β antisense gene-modified tumor cell vaccines are designed to exhibit increased immunogenicity due to reduced TGF-β expression in the tumor cells that comprise the vaccines. Vaccine Lucanix (belagenpumatucel-L) made from allogeneic non-small cell lung cancer (NSCLC) cell lines was well tolerated and brought survival advantages to NSCLC patients who were randomized within 12 weeks of completion of platinum-based chemotherapy and in those who had received prior radiation, as shown in a phase 3 trial which, however, failed to demonstrate a significant increase in survival in the overall patient population.⁸⁸² TGF-β antisense-modified autologous tumor cell vaccines have also been tested in advanced glioma and other solid tumors, respectively, in two phase 1 studies in which enhanced anti-tumor activity and improved survival were observed.^34,883 Notably, in the study among glioma patients, the most common treatment-related adverse events were delayed-type hypersensitivity-like reactions observed at the sites of the second and subsequent vaccinations in all patients. Some of these patients also experienced transient, flu-like symptoms consisting of musculoskeletal aches and pains and fatigue during the course of treatment.³⁴
TGF-β 反义基因修饰的肿瘤细胞疫苗被设计为由于构成疫苗的肿瘤细胞中 TGF-β 表达减少而表现出增强的免疫原性。由同种异体非小细胞肺癌 (NSCLC) 细胞系制成的疫苗 Lucanix (belagenpumatucel-L) 具有良好的耐受性，为完成铂类化疗后 12 周内随机分配的 NSCLC 患者以及接受过铂类化疗的患者带来了生存优势。先前的放射治疗，如第 3 期试验所示，但未能证明总体患者群体的生存率显着增加。 ⁸⁸² TGF-β 反义修饰的自体肿瘤细胞疫苗也在两项 1 期研究中分别在晚期神经胶质瘤和其他实体瘤中进行了测试，观察到抗肿瘤活性增强和生存率提高。 ^{34 , 883}值得注意的是，在神经胶质瘤患者的研究中，最常见的治疗相关不良事件是在所有患者第二次及后续疫苗接种部位观察到的迟发型超敏反应样反应。其中一些患者在治疗过程中还经历了短暂的流感样症状，包括肌肉骨骼疼痛和疲劳。 ³⁴

Targeting furin 靶向弗林蛋白酶

Convertase furin is a therapeutic target participating in the post-translational processing of TGF-β. Vigil (FANG or Gemogenovatucel-T) is an autologous tumor cell vaccine incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a bifunctional short-hairpin RNA (shRNA) targeting the expression of furin. A phase 1 study confirmed its safety and efficacy in various advanced solid tumors, with significant survival differences noted between patients who received less than four vaccinations and those who received no less than four vaccinations.⁸⁸⁴ A later phase 2b trial also demonstrated significant clinical benefit in homologous recombination proficient ovarian cancer (NCT02346747).⁸⁸⁵ Both studies reported no treatment-related serious adverse events, while the most common grade one and two adverse events related to study medication were local reactions at the injection site.
弗林蛋白酶转化酶是参与 TGF-β 翻译后加工的治疗靶点。 Vigil（FANG 或 Gemogenovatucel-T）是一种自体肿瘤细胞疫苗，包含编码粒细胞巨噬细胞集落刺激因子 (GMCSF) 的质粒和靶向弗林蛋白酶表达的双功能短发夹 RNA (shRNA)。一项一期研究证实了其在各种晚期实体瘤中的安全性和有效性，在接受少于四次疫苗接种的患者和接受不少于四次疫苗接种的患者之间观察到显着的生存差异。 ⁸⁸⁴后来的 2b 期试验也证明了同源重组熟练的卵巢癌具有显着的临床益处 (NCT02346747)。 ⁸⁸⁵两项研究均未报告与治疗相关的严重不良事件，而与研究药物相关的最常见的一级和二级不良事件是注射部位的局部反应。

Alteration of TGF-β activation
TGF-β 激活的改变

Targeting latent TGF-β complex
靶向潜在的 TGF-β 复合物

SRK-181 is an antibody that selectively binds to latent TGF-β1 to inhibit its activation. Co-administration of SRK-181 and anti-PD-1 antibody induced profound anti-tumor responses and survival benefit in mice, with increased infiltrating CD8+ T cells and decreased immunosuppressive myeloid cells observed in tumors refractory to anti-PD-1 treatment.⁸⁸⁶ The selective blockade of TGF-β1 by SRK-181 neither caused cardiac valvulopathy in rats as pan-TGFβ inhibitors might do nor did it induce cytokine release in human peripheral blood. Moreover, SRK-181 showed no effect on human platelet aggregation, activation, and binding.^886,887 The favorable safety profile displayed in these preclinical assessments supports the ongoing phase 1 trial of SRK-181 in patients with advanced cancers (NCT04291079).
SRK-181 是一种选择性结合潜在 TGF-β1 以抑制其激活的抗体。 SRK-181 和抗 PD-1 抗体联合给药可在小鼠中诱导显着的抗肿瘤反应和生存获益，在抗 PD-1 治疗难治的肿瘤中观察到浸润性 CD8+ T 细胞增加和免疫抑制性骨髓细胞减少。 ⁸⁸⁶ SRK-181 对 TGF-β1 的选择性阻断既不会像泛 TGFβ 抑制剂那样引起大鼠心脏瓣膜病，也不会诱导人外周血中细胞因子的释放。此外，SRK-181 对人血小板聚集、激活和结合没有影响。 ^{886 , 887}这些临床前评估中显示的良好安全性支持了正在进行的 SRK-181 在晚期癌症患者中的 1 期试验 (NCT04291079)。

Targeting GARP 针对 GARP

GARP expressed by Tregs, platelets, and endothelium functions to tether latent TGF-β complex to the cell surface for activation. Anti-GARP monoclonal antibody PIIO-1 proved to be an effective and safe strategy to block TGF-β activation in preclinical models, for it specifically bound to ligand-free GARP on Tregs but lacked recognition of GARP-latent TGF-β complex on platelets, actually avoiding the risk of platelet-related toxicities such as thrombocytopenia. More importantly, PIIO-1 showed therapeutic efficacy against both GARP+ and GARP- cancers alone or in combination with anti-PD-1 antibody, by preventing T cell exhaustion and enhancing CD8+ T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.⁸⁸⁸
由 Tregs、血小板和内皮细胞表达的 GARP 具有将潜在的 TGF-β 复合物束缚到细胞表面以进行激活的功能。抗 GARP 单克隆抗体 PIIO-1 被证明是临床前模型中阻断 TGF-β 激活的有效且安全的策略，因为它特异性结合 Tregs 上的无配体 GARP，但缺乏对血小板上 GARP 潜在 TGF-β 复合物的识别，实际上避免了血小板相关毒性的风险，例如血小板减少症。更重要的是，PIIO-1 通过防止 T 细胞耗竭并增强 CD8+ T 细胞迁移到 CXC 基序趋化因子受体 3 中的 TME，单独或与抗 PD-1 抗体组合对 GARP+ 和 GARP- 癌症显示出治疗功效。 CXCR3)依赖的方式。^第888章

Targeting αV integrins 靶向 αV 整合素

Integrins are regarded as the most important activators of TGF-β. Abituzumab (EMD 525797 or DI17E6) is an antibody against pan-αV integrins. In a phase 1/2 trial on KRAS wild-type metastatic colorectal cancer (NCT01008475), the progression-free survival (PFS) and response rates were similar among all groups in the intent-to-treat population comprising all patients randomized, although a trend toward improved overall survival (OS) was observed in the groups that received abituzumab treatment. However, exploratory analysis suggested that in patients with high αVβ6 expression, PFS and response rates might be increased with abituzumab therapy.⁸⁸⁹ This pan-αV integrin inhibitor was also found to inhibit prostate cancer-associated bone lesion formation in a randomized phase 2 trial (NCT01360840), although PFS was not significantly extended.⁸⁹⁰ Recently, abituzumab has been investigated in SSc-associated interstitial lung disease in a phase 2 trial (NCT02745145). However, the study was terminated prematurely due to slow enrollment and no meaningful conclusions could be drawn due to a small sample size.⁸⁹¹ The most commonly reported treatment-related adverse events of abituzumab included fatigue, headache, gastrointestinal disorders, as well as abnormal biochemistry and hematology values.^889,890,892
整合素被认为是TGF-β最重要的激活剂。 Abituzumab（EMD 525797 或 DI17E6）是一种针对泛 αV 整联蛋白的抗体。在一项针对 KRAS 野生型转移性结直肠癌 (NCT01008475) 的 1/2 期试验中，由随机分组的所有患者组成的意向治疗人群中所有组的无进展生存期 (PFS) 和缓解率相似，尽管在接受阿比珠单抗治疗的组中观察到总生存期 (OS) 改善的趋势。然而，探索性分析表明，在 αVβ6 高表达的患者中，阿比珠单抗治疗可能会提高 PFS 和缓解率。 ⁸⁸⁹在一项随机 2 期试验 (NCT01360840) 中，还发现这种泛 αV 整合素抑制剂可抑制前列腺癌相关骨病变的形成，但 PFS 并未显着延长。 ⁸⁹⁰最近，阿比珠单抗已在 2 期试验中研究了 SSc 相关间质性肺疾病 (NCT02745145)。然而，由于入组速度缓慢，该研究提前终止，并且由于样本量较小，无法得出有意义的结论。 ⁸⁹¹最常见报告的阿比珠单抗治疗相关不良事件包括疲劳、头痛、胃肠道疾病以及生化和血液学值异常。 ^{889、890、892​​}

Cilengitide (EMD 121974, NSC 707544) is a selective αvβ3 and αvβ5 integrin inhibitor which has been evaluated for therapeutic efficacy in NSCLC (NCT00842712),^893,894 head and neck SCC (NCT00705016),⁸⁹⁵ glioblastoma (NCT00689221, NCT00813943, and NCT01124240),^{896,897,898,899,900,901,902,903} melanoma,⁹⁰⁴ pancreatic cancer,⁹⁰⁵ and prostate cancer^906,907 in a series of phase 2 studies and one phase 3 study. Although cilengitide failed to demonstrate significant clinical benefits in these studies on tumors, it might be a novel treatment for fibrotic diseases as relevant preclinical studies suggested.^908,909 Notably, the adverse events possibly related to cilengitide treatment included fatigue, arthralgia, lymphopenia, and gastrointestinal disorders.^{893,897,899,900,904,906,907} Furthermore, an inhibitor of pan-integrins and TGF-β known as GLPG-0187 was proved to enhance T cell killing of colorectal cancer cells in vitro, possibly by suppressing TGF-β-mediated PD-L1 upregulation.^910,911
Cilengitide (EMD 121974, NSC 707544) 是一种选择性 αvβ3 和 αvβ5 整合素抑制剂，已针对 NSCLC (NCT00842712) ^{、 893、894}头颈 SCC (NCT00705016)、 ⁸⁹⁵胶质母细胞瘤 (NCT00689221、 3、NCT01124240） 、 ^{896 、 897 、 898 、 899 、 900 、 901 、 902 、 903}黑色素瘤、 ⁹⁰⁴胰腺癌、 ⁹⁰⁵和前列腺癌^{906 、 907}在一系列 2 期研究和一项 3 期研究中。尽管西仑吉肽在这些肿瘤研究中未能证明显着的临床益处，但正如相关临床前研究表明的那样，它可能是纤维化疾病的一种新疗法。 ^{908 , 909}值得注意的是，可能与西仑吉肽治疗相关的不良事件包括疲劳、关节痛、淋巴细胞减少和胃肠道疾病。 ^{893 , 897 , 899 , 900 , 904 , 906 , 907}此外，一种称为 GLPG-0187 的泛整合素和 TGF-β 抑制剂被证明可以在体外增强 T 细胞对结直肠癌细胞的杀伤作用，可能是通过抑制 TGF-β -介导的PD-L1上调。 ^{910 , 911}

Targeting TSP-1 靶向 TSP-1

TSP-1 can directly activate all three TGF-β isoforms independent of other activators or cellular activity. The conserved LSKL sequence in LAP which is recognized by TSP-1 can be synthesized as peptides to block TSP-1-mediated TGF-β activation. Pre-clinical studies suggested that treatment of LSKL or relevant tripeptide SRI31277 could be novel therapeutic strategies for various cardiovascular diseases,⁹¹² pulmonary diseases,⁹¹³ renal diseases,^914,915,916 nervous diseases,^917,918 fibrotic diseases,^919,920,921 wound healing,^922,923 and tumors.^924,925,926 Moreover, TSP-1 antisense oligonucleotides were successfully developed and applied to inhibit TGF-β activation in a rat model of mesangial proliferative glomerulonephritis, demonstrating a remarkable prevention against renal fibrosis.⁹²⁷
TSP-1 可以直接激活所有三种 TGF-β 亚型，独立于其他激活剂或细胞活性。 LAP 中被 TSP-1 识别的保守 LSKL 序列可以合成肽来阻断 TSP-1 介导的 TGF-β 激活。临床前研究表明，LSKL或相关三肽SRI31277的治疗可能成为多种心血管疾病、 ⁹¹²肺部疾病、 ⁹¹³肾脏疾病^{、 914、915、916神经}疾病^{、 917、918}纤维化疾病^{、 919、920、921的}新治疗策略^{922 、第923章}伤口愈合和肿瘤。 ^{924 , 925 , 926}此外，TSP-1 反义寡核苷酸已成功开发并应用于抑制系膜增生性肾小球肾炎大鼠模型中的 TGF-β 活化，显示出显着的预防肾纤维化的作用。 ⁹²⁷

Alteration of TGF-β signaling
TGF-β信号传导的改变

Targeting TGF-β ligands 靶向 TGF-β 配体

A TGF-β2-enriched polymeric dietary supplement known as Modulen (CT3211) was effective in inducing earlier remission of inflammatory bowel diseases (IBDs) including both Crohn’s disease and UC with significant improvements in endoscopic and histologic appearances, mucosal cytokine parameters, C-reactive protein (CRP) values, erythrocyte sedimentation rates (ESRs), serum albumin levels, as well as weight and height scores in the patients.^{928,929,930,931} Notably, an exclusive Modulen diet was more efficient than steroids to induce mucosal healing in children with Crohn’s disease, possibly due to its additional advantage in regulating intestinal microbiota (NCT00265772).^932,933 Moreover, a pre-operative polymeric diet enriched with TGF-β2 was able to decrease post-operative complications after surgery for complicated ileocolonic Crohn’s disease.⁹³⁴ The side effects of Modulen were mild, including abdominal pain, flatulence, nausea, and vomiting.^928,932,934 In mouse models, oral TGF-β supplementation also showed beneficial effects on food allergy prevention.^935,936,937 In fact, it is believed that the presence of TGF-β in breast milk can protect the progeny from several allergic diseases such as asthma,⁹³⁸ eczema,⁹³⁹ and food allergy.⁹⁴⁰
富含 TGF-β2 的聚合物膳食补充剂，称为 Modulen (CT3211)，可有效诱导炎症性肠病 (IBD) 的早期缓解，包括克罗恩病和 UC，并显着改善内镜和组织学外观、粘膜细胞因子参数、C 反应性蛋白质（CRP）值、红细胞沉降率（ESR）、血清白蛋白水平以及患者的体重和身高评分。 ^{928 , 929 , 930 , 931}值得注意的是，独家 Modulen 饮食比类固醇更有效地诱导克罗恩病儿童的粘膜愈合，这可能是由于其在调节肠道微生物群方面的额外优势 (NCT00265772)。 ^{932 , 933}此外，富含 TGF-β2 的术前聚合饮食能够减少复杂性回结肠克罗恩病手术后的术后并发症。 ⁹³⁴ Modulen 的副作用很轻微，包括腹痛、胀气、恶心和呕吐。 ^{928 , 932 , 934}在小鼠模型中，口服 TGF-β 补充剂也显示出对预防食物过敏的有益作用。^{第935、936、937事实上}，人们相信母乳中存在的TGF-β可以保护后代免受多种过敏性疾病的侵害，例如哮喘、^湿疹、 ⁹³⁹和食物过敏。 ⁹⁴⁰

Recombinant human TGF-β3 known as avotermin (Juvista) is a potential therapy for the improvement of cutaneous scarring. In a series of phase 1/2 studies (NCT00847925, NCT00847795, NCT00629811, NCT00432211, NCT00594581, and NCT00430326), visual assessment of scar formation revealed that, in contrast to placebo, intradermal avotermin could significantly improve total scar scores which were derived from a visual analog scale to assess how closely scars resembled normal skin. The results were further confirmed by histological assessments that scars treated with avotermin showed better organized ECM of the papillary and reticular dermis. The incidence of adverse events at wound sites, including infection, exudate, erythema, pain, burning, itching, and thickening was low and similar for avotermin and controls.^{941,942,943,944} Although the other two TGF-β isoforms, TGF-β1 and TGF-β2, showed no therapeutic activity of scarring, they were found to improve and accelerate the healing of cutaneous wounds in animal models as well as clinical patients.^{304,306,307,317,321,334,945} Moreover, TGF-β also showed therapeutic potential for tissue regeneration,^329,946,947 inflammatory diseases,^676,687,948 and influenza⁹⁴⁹ as shown in relevant preclinical models.
重组人 TGF-β3 称为阿沃特明 (Juvista)，是一种改善皮肤疤痕的潜在疗法。在一系列 1/2 期研究（NCT00847925、NCT00847795、NCT00629811、NCT00432211、NCT00594581 和 NCT00430326）中，对疤痕形成的视觉评估显示，与安慰剂相比，皮内阿沃特明可以显着改善总疤痕评分，该评分来自于视觉模拟量表来评估疤痕与正常皮肤的相似程度。组织学评估进一步证实了阿伏特明治疗的疤痕显示乳头状和网状真皮组织更好的 ECM。阿沃特明和对照组的伤口部位不良事件发生率较低，包括感染、渗出物、红斑、疼痛、烧灼感、瘙痒和增厚，且相似。 ^{941 , 942 , 943 , 944}虽然另外两种 TGF-β 异构体 TGF-β1 和 TGF-β2 没有表现出疤痕治疗活性，但在动物模型和临床研究中发现它们可以改善和加速皮肤伤口的愈合患者。 ^{304、306、307、317、321、334、945此外， TGF - β还}显示出对组织再生^{、 329、946、947炎症}性疾病、 ^{676、687、948和流感949}的治疗潜力，如相关临床前模型所示。

TGF-β neutralizing antibodies and ligand traps can block the binding of TGF-β to its receptors. Fresolimumab (GC1008), a monoclonal antibody that neutralizes all three TGF-β isoforms demonstrated acceptable safety and preliminary evidence of anti-tumor activity in a phase 1 study on advanced malignant melanoma and renal cell carcinoma (NCT00356460).⁹⁵⁰ In a phase 2 trial (NCT01401062), a higher dose of fresolimumab is associated with longer median OS as well as improved peripheral blood mononuclear cell counts and boosted central memory CD8+ T cell levels in metastatic breast cancer patients receiving radiotherapy.⁹⁵¹ Fresolimumab also showed therapeutic effects on SSc with decreased biomarkers of skin fibrosis and improved clinical symptoms in the patients in a phase 1 study (NCT01284322).⁹⁵² Moreover, a phase 1 study evaluated the safety of fresolimumab in patients with treatment-resistant primary focal segmental glomerulosclerosis and the good tolerability supported additional evaluation in larger randomized dose-ranging clinical trials.⁹⁵³ Notably, the major drug-related adverse events of fresolimumab were skin disorders, bleeding episodes, and anemia. Skin toxicity was particularly significant and tumor patients assigned to high doses of treatment even developed skin tumors, including keratoacanthoma, basal cell carcinoma, and SCC.^{950,951,952,953,954} Another anti-TGF-β monoclonal antibody known as NIS793 was well tolerated alone or in combination with anti-PD-1 antibody in patients with advanced solid tumors in a phase 1 study (NCT02947165). Treatment-related adverse events of all patients in the study were mostly skin toxicity and gastrointestinal events, and no dose-limiting toxicities were observed during dose escalation. Notably, biomarker analyses in the study showed evidence of systemic target engagement, local signaling inhibition, and tumor immune activation.⁹⁵⁵ Apart from tumors, a recombinant human anti-TGF-β1 antibody known as CAT-192 was evaluated in the treatment of early-stage diffuse cutaneous SSc but showed no evidence of efficacy in the pilot phase 1/2 study. The most commonly reported adverse events in the study affected the gastrointestinal, musculoskeletal, respiratory, and skin systems, but none of them were considered to be related to the treatment.⁹⁵⁶ Moreover, a phase 2 study assessing the safety and efficacy of TGF-β1 monoclonal antibody in patients with diabetic nephropathy was terminated early for futility (NCT01113801). The frequencies of the various categories of adverse effects in this study were generally similar between the treatment and placebo groups.⁹⁵⁷ Furthermore, monotherapy of a selective TGF-β1/3 trap known as AVID200 in a population of patients with an advanced stage of myelofibrosis in a phase 1b trial resulted in limited toxicity as well as improvements in spleen size, symptom benefit, and platelet counts (NCT03895112). Remarkably, platelet count increase was a therapeutic effect not observed with other myelofibrosis therapies, suggesting a potential advantage of AVID200 treatment. Adverse events that occurred during the study regardless of attribution mainly included pruritus, fatigue, abdominal pain, anemia, and thrombocytopenia.⁹⁵⁸ Additionally, other potential applications of neutralizing TGF-β antibodies suggested by pre-clinical studies include wound healing,^334,959,960 prostatic hyperplasia,⁹⁶¹ pulmonary diseases,^962,963 cardiovascular diseases,^564,964 musculoskeletal diseases,^{965,966,967,968} inflammatory diseases,^969,970 and Chagas disease (Trypanosoma cruzi infection).⁹⁷¹
TGF-β 中和抗体和配体陷阱可以阻断 TGF-β 与其受体的结合。 Fresolimumab (GC1008) 是一种中和所有三种 TGF-β 同工型的单克隆抗体，在针对晚期恶性黑色素瘤和肾细胞癌的 1 期研究 (NCT00356460) 中表现出可接受的安全性和抗肿瘤活性的初步证据。 ⁹⁵⁰在一项 2 期试验 (NCT01401062) 中，较高剂量的 fresolimumab 与接受放疗的转移性乳腺癌患者的中位 OS 较长、外周血单核细胞计数改善和中央记忆 CD8+ T 细胞水平升高相关。在一项 1 期研究 (NCT01284322) 中， ⁹⁵¹ Fresolimumab 还显示出对 SSc 的治疗效果，可减少皮肤纤维化的生物标志物并改善患者的临床症状。 ⁹⁵²此外，一项 1 期研究评估了 fresolimumab 在难治性原发性局灶节段性肾小球硬化患者中的安全性，良好的耐受性支持在更大规模的随机剂量范围临床试验中进行额外评估。 ⁹⁵³值得注意的是，fresolimumab 的主要药物相关不良事件是皮肤病、出血事件和贫血。皮肤毒性尤其显着，接受高剂量治疗的肿瘤患者甚至出现皮肤肿瘤，包括角化棘皮瘤、基底细胞癌和鳞状细胞癌。 ^{950、951、952、953、954另一种称为NIS793}的抗 TGF-β 单克隆抗体在 1 期研究 (NCT02947165) 中，单独使用或与抗 PD-1 抗体联合使用，在晚期实体瘤患者中具有良好的耐受性。 研究中所有患者的治疗相关不良事件主要是皮肤毒性和胃肠道事件，剂量递增期间未观察到剂量限制性毒性。值得注意的是，该研究中的生物标志物分析显示了系统靶点参与、局部信号抑制和肿瘤免疫激活的证据。 ⁹⁵⁵除肿瘤外，还评估了一种重组人抗 TGF-β1 抗体（称为 CAT-192）治疗早期弥漫性皮肤 SSc 的效果，但在 1/2 期试验研究中没有显示出疗效的证据。研究中最常见的不良事件影响胃肠道、肌肉骨骼、呼吸和皮肤系统，但没有一个被认为与治疗有关。 ⁹⁵⁶此外，一项评估 TGF-β1 单克隆抗体在糖尿病肾病患者中的安全性和有效性的 2 期研究因无效而提前终止 (NCT01113801)。本研究中治疗组和安慰剂组中各类不良反应的发生率总体相似。 ⁹⁵⁷此外，在 1b 期试验中，选择性 TGF-β1/3 陷阱（称为 AVID200）对晚期骨髓纤维化患者进行单一疗法，产生了有限的毒性，并改善了脾脏大小、症状益处和血小板计数（NCT03895112）。值得注意的是，血小板计数增加是其他骨髓纤维化疗法未观察到的治疗效果，表明 AVID200 治疗的潜在优势。研究期间发生的不良事件（无论归因如何）主要包括瘙痒、疲劳、腹痛、贫血和血小板减少。⁹⁵⁸此外，临床前研究表明中和 TGF-β 抗体的其他潜在应用包括伤口^{愈合、 334、959、960}前列腺增生、 ⁹⁶¹肺部疾病^{、 962、963}心血管疾病^{、 564、964}肌肉骨骼疾病、 ^{965、966 、第967章、第968章}炎性疾病，^{第969章、第970章}、恰加斯病（克氏锥虫感染）。^第971章

Bifunctional antibody-ligand traps containing the extracellular domain of TβRII can target both TGF-β and immune checkpoints. In preclinical studies, both the anti-CTL associated protein (CTLA)-4-TβRII chimera and the anti-PD-L1-TβRII chimera exhibited superior anti-tumor efficacy compared with their parent immune checkpoint inhibitors.⁹⁷² Bintrafusp alfa (M7824), a bifunctional fusion protein targeting both TGF-β and PD-L1 was assessed in several phase 1 trials (NCT02699515, NCT02517398, NCT02699515, and NCT04247282). The results showed that bintrafusp alfa had encouraging efficacy in NSCLC,⁹⁷³ gastric cancer,⁹⁷⁴ biliary tract cancer,⁹⁷⁵ as well as human papillomavirus (HPV)-unrelated head and neck cancer in which enhanced tumor antigen-specific immunity has been observed.⁹⁷⁶ Similar to fresolimumab, the treatment-related adverse events of bintrafusp alfa included fatigue, colitis, bleeding, anemia, hypokalemia, lipase increase, hepatic function abnormalities, as well as several skin disorders from rash, hyperkeratosis, to keratoacanthoma and SCC.^{973,974,975,976,977} BR102 is another bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. The efficacy and safety of BR102 demonstrated in preclinical characterization supported its further clinical development for anti-cancer therapy.⁹⁷⁸ Notably, the bifunctional antibody-ligand traps have inspired the development of chimeric antigen receptor (CAR)-T cells secreting bispecific trap protein, which co-targets PD-1 and TGF-β to enhance anti-tumor efficacy as shown in mouse models.⁹⁷⁹
含有 TβRII 胞外域的双功能抗体-配体陷阱可以同时靶向 TGF-β 和免疫检查点。在临床前研究中，与母体免疫检查点抑制剂相比，抗CTL相关蛋白（CTLA）-4-TβRII嵌合体和抗PD-L1-TβRII嵌合体均表现出更优异的抗肿瘤功效。 ⁹⁷² Bintrafusp alfa (M7824) 是一种同时靶向 TGF-β 和 PD-L1 的双功能融合蛋白，在多项 1 期试验（NCT02699515、NCT02517398、NCT02699515 和 NCT04247282）中进行了评估。^第973章胃癌，^第974章胆道癌，^第975章976与 fresolimumab 类似，bintrafusp alfa 的治疗相关不良事件包括疲劳、结肠炎、出血、贫血、低钾血症、脂肪酶增加、肝功能异常，以及皮疹、角化过度、角化棘皮瘤和鳞状细胞癌等多种皮肤疾病。 ^{973 , 974 , 975 , 976 , 977} BR102是另一种同时靶向PD-L1和TGF-β的双功能融合蛋白。临床前表征中所证明的 BR102 的功效和安全性支持其抗癌治疗的进一步临床开发。⁹⁷⁸值得注意的是，双功能抗体-配体陷阱激发了分泌双特异性陷阱蛋白的嵌合抗原受体 (CAR)-T 细胞的开发，该蛋白共同靶向 PD-1 和 TGF-β 以增强抗肿瘤功效，如小鼠模型所示。^第979章

Furthermore, LAP, TβRIII (β-glycan), and decorin can bind to TGF-β as natural inhibitors. They have shown treatment effects in preclinical models of wound healing,^{980,981,982,983} cardiovascular diseases,^{984,985,986,987,988,989} nervous diseases,^990,991,992 renal diseases,^{993,994,995,996} fibrotic diseases,^{997,998,999,1000} tuberculosis,¹⁰⁰¹ and tumors^{1002,1003,1004,1005} and thus warrant further development.
此外，LAP、TβRIII（β-聚糖）和核心蛋白聚糖可以作为天然抑制剂与 TGF-β 结合。他们在^{伤口愈合、 980、981、982、983}心血管^{疾病、 984、985、986、987、988、989神经疾病、 990、991、992肾脏疾病、 993、994、995 、 996}纤维化疾病， ^{997、998、999、1000结核病、 1001和肿瘤1002、1003、1004、1005 ，因此}需要进一步开发。

Targeting TβRs 靶向 TβR

TGF-β-insensitive CAR-T cells armored with dominant-negative TβRII showed preliminary evidence for early anti-tumor function in prostate cancer, including a biomarker decline among approximately 30% of the patients in a phase 1 trial (NCT03089203). This strategy which is considered generally feasible, despite no partial response being observed in the study, and safe, with study-related serious adverse events mostly being cytokine release syndrome, warrants further validation and investigation.¹⁰⁰⁶ Dominant-negative TβRII can also enhance the anti-tumor efficacy of DC vaccines, manifested by powerful tumor-specific CTL responses, inhibited tumor development, and prolonged survival times in mouse models.^1007,1008 Moreover, dominant-negative TβRII showed great potential for reducing hypertrophic scars as in rabbit ear models.¹⁰⁰⁹
带有显性失活 TβRII 的 TGF-β 不敏感 CAR-T 细胞显示出前列腺癌早期抗肿瘤功能的初步证据，包括在 1 期试验 (NCT03089203) 中约 30% 的患者生物标志物下降。尽管在研究中没有观察到部分反应，但该策略被认为是普遍可行的，并且是安全的，与研究相关的严重不良事件主要是细胞因子释放综合征，值得进一步验证和研究。 ¹⁰⁰⁶显性阴性 TβRII 还可以增强 DC 疫苗的抗肿瘤功效，表现为强大的肿瘤特异性 CTL 反应，抑制肿瘤发展并延长小鼠模型的生存时间。 ^{1007 , 1008}此外，显性失活 TβRII 在减少兔耳模型中的肥厚性疤痕方面显示出巨大潜力。 ¹⁰⁰⁹

Many small-molecule inhibitors have been developed to suppress the kinase activity of TβRI. In a series of phase 2 studies, a TβRI kinase inhibitor known as galunisertib (LY2157299) showed preliminary efficacy in patients with myelodysplastic syndromes (MDS) (NCT02008318),¹⁰¹⁰ NSCLC (NCT02423343),¹⁰¹¹ hepatocellular carcinoma (NCT01246986),^1012,1013 rectal cancer (NCT02688712),¹⁰¹⁴ and pancreatic cancer,¹⁰¹⁵ but failed to demonstrate clinical benefit in patients with glioma (NCT01582269 and NCT01220271).^1016,1017 The most common adverse events related to galunisertib treatment included fatigue, pyrexia, anemia, nausea, vomiting, diarrhea, and abdominal pain.^{1010,1013,1017} Despite comprehensive cardiovascular monitoring for galunisertib did not detect medically relevant cardiac toxicity in cancer patients,¹⁰¹⁸ galunisertib-related uncontrolled cytokine release was reported in patients with advanced solid tumors in a phase 1 trial (NCT01646203).¹⁰¹⁹ Other TβRI kinase inhibitors such as SM16, SD-208, NP-40208, SB-431542, LY3200882, LY364947, and vactosertib (EW-7197) also showed therapeutic potential in pre-clinical studies on tumors^{1020,1021,1022,1023,1024,1025,1026} as well as many other diseases such as cardiovascular diseases,^{565,1027,1028,1029,1030} renal diseases,¹⁰³¹ ophthalmic diseases,¹⁰³² skeletal diseases,¹⁰³³ fibrotic diseases,^{1034,1035,1036} inflammatory diseases,^{1037,1038,1039} Chagas disease,^1040,1041 coronavirus disease 2019 (COVID-19),¹⁰⁴² and wound healing.^{1043,1044,1045}
许多小分子抑制剂已被开发来抑制 TβRI 的激酶活性。在一系列 2 期研究中，一种名为 galunisertib (LY2157299) 的 TβRI 激酶抑制剂对骨髓增生异常综合征 (MDS) (NCT02008318)、 ¹⁰¹⁰ NSCLC (NCT02423343)、 ¹⁰¹¹肝细胞癌 (NCT01246986) ^{、 1012、1013}直肠癌患者显示出初步疗效。癌症（NCT02688712）， ¹⁰¹⁴和胰腺癌， ¹⁰¹⁵ ，但未能证明对神经胶质瘤患者有临床益处（NCT01582269 和 NCT01220271）。 ^{1016 , 1017}与 galunisertib 治疗相关的最常见不良事件包括疲劳、发热、贫血、恶心、呕吐、腹泻和腹痛。^{第1010章1013章 第1017章 尽管对galunisertib进行的全面心血管监测并未检测到癌症患者的医学相关心脏毒性，但在一项1期试验（NCT01646203）中，在晚期}实体瘤患者中报告了与galunisertib相关的不受控制的细胞因子释放（NCT01646203）。¹⁰¹⁹其他 TβRI 激酶抑制剂，如 SM16、SD-208、NP-40208、SB-431542、LY3200882、LY364947 和 vactosertib (EW-7197) 也在肿瘤临床前研究中显示出治疗潜力^{1020 、 1021 、 1022 、 1023 , 1024 , 1025 , 1026}以及许多其他疾病，如心血管疾病， ^{565 , 1027 , 1028 , 1029 , 1030}肾脏疾病， ¹⁰³¹眼科疾病， ¹⁰³²骨骼疾病， ¹⁰³³纤维化疾病， ^{1034 , 1035 , 1036}炎症性疾病， ^{037 、 1038 、 1039}恰加斯病、 ^{1040 、 1041} 2019 年冠状病毒病 (COVID-19)、 ¹⁰⁴²和伤口愈合。^{1043、1044、1045​​}

Targeting SMADs 针对 SMAD

An oral SMAD7 antisense oligonucleotide known as mongersen (GED-0301) showed promising results in patients with active Crohn’s disease in phase 1 and 2 phase trials, but further phase 3 study failed due to lack of clinical benefit (EudraCT 2009-012465-66, EudraCT 2011-002640-27, and NCT02596893).^{1046,1047,1048} Meanwhile, SMAD3 antisense oligonucleotide treatment was found to improve flexor tendon repair in mice and might have possible therapeutic applications in clinical practice.⁸⁷⁷
一种名为 mongersen 的口服 SMAD7 反义寡核苷酸 (GED-0301) 在 1 期和 2 期试验中对活动性克罗恩病患者显示出有希望的结果，但进一步的 3 期研究因缺乏临床益处而失败 (EudraCT 2009-012465-66， EudraCT 2011-002640-27 和 NCT02596893）。 ^{1046 , 1047 , 1048}同时，SMAD3 反义寡核苷酸治疗被发现可以改善小鼠的屈肌腱修复，并可能在临床实践中具有潜在的治疗应用。^第877章

Moreover, a small-molecule SMAD3 inhibitor known as specific inhibitor of SMAD3 (SIS3) has shown pre-clinical therapeutic efficacy in wound healing,¹⁰⁴⁹ cardiovascular diseases,^{569,1050,1051} nervous diseases,¹⁰⁵² renal diseases,^1053,1054 skeletal diseases,¹⁰⁵⁵ fibrotic diseases,^1056,1057 inflammatory diseases,^1039,1058 type 2 diabetes,^1059,1060 and tumors,^1061,1062 suggesting a novel approach that could be further tested to treat clinical patients.
此外，一种被称为SMAD3特异性抑制剂（SIS3）的小分子SMAD3抑制剂已在伤口愈合、 ¹⁰⁴⁹心血管^{疾病、 569、1050、1051}神经疾病、 ¹⁰⁵²肾脏疾病^{、 1053、1054}骨骼疾病、^第1055章纤维化疾病^{， 1056、1057}炎症性疾病^{， 1039、1058} 2型糖尿病^{， 1059、1060}和肿瘤^{， 1061、1062}提出了一种可以进一步测试以治疗临床患者的新方法。

Furthermore, several SMAD-binding peptide aptamers have been developed to selectively inhibit the binding between SMADs and their interacting factors.¹⁰⁶³ An aptamer containing the SMAD-binding domain of transcription factor lymphoid enhancer-binding factor 1 (LEF1) can suppress tumor cell proliferation by inhibiting the interaction between SMAD4 and LEF/T cell-specific factor (TCF) to suppress MYC expression.¹⁰⁶⁴ Other aptamers that bind specifically to R-SMADs through the SMAD-binding domain from SARA can impair the formation of functional SMAD oligomers to inhibit TGF-β-induced EMT.^1065,1066 Moreover, aptamers that disrupt the interaction between SMAD and transcription coactivator yes-associated protein (YAP) have been designed for bone tumor therapy.¹⁰⁶⁷
此外，已经开发了几种 SMAD 结合肽适体来选择性抑制 SMAD 与其相互作用因子之间的结合。 ¹⁰⁶³含有转录因子淋巴增强子结合因子 1 (LEF1) SMAD 结合域的适体可以通过抑制 SMAD4 与 LEF/T 细胞特异性因子 (TCF) 之间的相互作用来抑制 MYC 表达，从而抑制肿瘤细胞增殖。 ¹⁰⁶⁴其他通过 SARA 的 SMAD 结合域与 R-SMAD 特异性结合的适体可以损害功能性 SMAD 寡聚体的形成，从而抑制 TGF-β 诱导的 EMT。 ^{1065 , 1066}此外，破坏 SMAD 和转录共激活因子 yes 相关蛋白 (YAP) 之间相互作用的适体已被设计用于骨肿瘤治疗。 ¹⁰⁶⁷

TGF-β signaling is so extensively and indispensably involved in a large number of biological processes that it has attracted great interest and attention over the past decades during which relevant knowledge has exploded in the fields of health, disease, and therapeutics. However, there are still some specific issues that have not been fully elucidated, while some previous knowledge is facing updates and challenges.
TGF-β信号传导如此广泛且不可或缺地参与大量生物过程，以至于在过去几十年中引起了人们的极大兴趣和关注，在此期间，相关知识在健康、疾病和治疗领域得到了爆炸式增长。但仍有一些具体问题尚未完全阐明，一些以往的认识正面临更新和挑战。

Studies on embryonic development and wound healing have revealed the isoform-specific roles of TGF-β which remain poorly aware in other fields of research, as studies on immune homeostasis, fibrotic diseases, and tumor development so far have focused on the most abundant TGF-β1 isoform in particular. Since all TGF-β isoforms are believed to signal through the same receptors and downstream pathways, the causes of the differences in biological effects between isotypes have not been fully understood. Moreover, since a natural TGF-β heterodimer containing one TGF-β1 monomer and one TGF-β2 monomer has long been discovered,^12,1068 it would be very interesting to identify and characterize novel TGF-β heterodimers in the future. Furthermore, with the discovery and study of TGF-β superfamily which also includes polypeptides structurally similar to TGF-β such as nodal, myostatin, inhibins, activins, Müllerian-inhibiting substance (MIS), bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), researchers have realized that TGF-β can also signal through pathways ‘specific’ to other TGF-β superfamily members, for example, via receptors ALK1/2/3 and transcription factors SMAD1/5/8.^{1069,1070,1071,1072,1073} The significance of the signaling crosstalk within the TGF-β superfamily also warrants future exploration. Notably, Reblozyl (luspatercept or ACE-536), a ligand trap that contains the extracellular domain of human activin receptor type IIB (ActRIIB) to inhibit GDF11-mediated SMAD2/3 signaling has been approved by the US Federal Drug Agency (FDA) for the treatment of anemia in adult patients with β-thalassemia or with MDS.
对胚胎发育和伤口愈合的研究揭示了 TGF-β 的亚型特异性作用，但其他研究领域对此仍知之甚少，因为迄今为止对免疫稳态、纤维化疾病和肿瘤发展的研究都集中在最丰富的 TGF-β 上。尤其是β1亚型。由于所有 TGF-β 同种型都被认为通过相同的受体和下游途径发出信号，因此同种型之间生物学效应差异的原因尚未完全了解。此外，由于含有一种 TGF-β1 单体和一种 TGF-β2 单体的天然 TGF-β 异二聚体早已被发现， ^{12 , 1068}未来鉴定和表征新型 TGF-β 异二聚体将非常有趣。此外，随着TGF-β超家族的发现和研究，该家族还包括与TGF-β结构相似的多肽，如结节、肌生长抑制素、抑制素、激活素、苗勒氏管抑制物质（MIS）、骨形态发生蛋白（BMP）以及生长和生长因子。除了分化因子 (GDF) 之外，研究人员还意识到 TGF-β 还可以通过其他 TGF-β 超家族成员“特异”的途径发出信号，例如通过受体 ALK1/2/3 和转录因子 SMAD1/5/8。 ^{1069 , 1070 , 1071 , 1072 , 1073} TGF-β 超家族内信号串扰的重要性也值得未来探索。值得注意的是，Reblozyl（luspatercept 或 ACE-536）是一种配体捕获剂，含有人 IIB 型激活素受体 (ActRIIB) 的胞外结构域，可抑制 GDF11 介导的 SMAD2/3 信号传导，已获得美国联邦药物管理局 (FDA) 批准用于治疗治疗患有β-地中海贫血或MDS的成年患者的贫血。

As for TGF-β-targeting therapy, the efficacy and safety of treatment are always issues of concern. The current lack of systematic studies on the dural roles of TGF-β in wound healing, infectious diseases, and tumor development may hinder the development of related therapeutics. Given the extensive impacts of TGF-β on a lot of biological processes, the development of TGF-β isoform-specific therapies and SMAD-binding peptide aptamers is expected to cause less adverse effects through more precise targeting. Moreover, the identification of the applicable population for each therapeutic approach is also important for better efficacy and less toxicity. Serum and tissue levels of TGF-β have shown potential as predictors or indicators of the development,^{1074,1075,1076,1077} complication,^{1078,1079,1080} response,^{1081,1082,1083,1084} recurrence,^{1085,1086,1087} and outcomes^{1088,1089,1090} of various kinds of diseases, meanwhile, bioinformatic tools of TGF-β signaling-related gene expression signatures have also been developed for patient stratification.^863,1091 But so far, TGF-β or related factors as clinical biomarkers still need further development and assessment.
对于TGF-β靶向治疗，治疗的有效性和安全性一直是人们关注的问题。目前缺乏关于 TGF-β 在伤口愈合、感染性疾病和肿瘤发展中的硬脑膜作用的系统研究，可能会阻碍相关疗法的发展。鉴于 TGF-β 对许多生物过程的广泛影响，TGF-β 异构体特异性疗法和 SMAD 结合肽适体的开发预计将通过更精确的靶向来减少不良反应。此外，确定每种治疗方法的适用人群对于提高疗效和降低毒性也很重要。 TGF-β的血清和组织水平已显示出^{作为发展、 1074、1075、1076、1077并发症、 1078、1079、1080反应、 1081、1082、1083、1084复发、 1085、1086、1087和}各种疾病的结果^{1088 , 1089 , 1090} ，同时，还开发了 TGF-β 信号传导相关基因表达特征的生物信息学工具用于患者分层。 ^{863 , 1091}但迄今为止，TGF-β或相关因子作为临床生物标志物仍需要进一步的开发和评估。

To summarize, this review focuses on the multiple roles of TGF-β in health and disease while emphasizing the mechanisms of TGF-β production, activation, signaling, as well as corresponding therapeutic strategies. These understandings might be instructive for the basic and applied research of relevant topics in the future.
综上所述，本综述重点关注 TGF-β 在健康和疾病中的多重作用，同时强调 TGF-β 产生、激活、信号传导的机制以及相应的治疗策略。这些认识对于未来相关课题的基础和应用研究可能具有指导意义。