Monash Institute of Medical Research, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.
Vitam Horm. 2011;85:255-97. doi: 10.1016/B978-0-12-385961-7.00013-5.
The activins are members of the transforming growth factor β superfamily with broad and complex effects on cell growth and differentiation. Activin A has long been known to be a critical regulator of inflammation and immunity, and similar roles are now emerging for activin B, with which it shares 65% sequence homology. These molecules and their binding protein, follistatin, are widely expressed, and their production is increased in many acute and chronic inflammatory conditions. Synthesis and release of the activins are stimulated by inflammatory cytokines, Toll-like receptor ligands, and oxidative stress. The activins interact with heterodimeric serine/threonine kinase receptor complexes to activate SMAD transcription factors and the MAP kinase signaling pathways, which mediate inflammation, stress, and immunity. Follistatin binds to the activins with high affinity, thereby obstructing the activin receptor binding site, and targets them to cell surface proteoglycans and lysosomal degradation. Studies on transgenic mice and those with gene knockouts, together with blocking studies using exogenous follistatin, have established that activin A plays critical roles in the onset of cachexia, acute and chronic inflammatory responses such as septicemia, colitis and asthma, and fibrosis. However, activin A also directs the development of monocyte/macrophages, myeloid dendritic cells, and T cell subsets to promote type 2 and regulatory immune responses. The ability of both endogenous and exogenous follistatin to block the proinflammatory and profibrotic actions of activin A has led to interest in this binding protein as a potential therapeutic for limiting the severity of disease and to improve subsequent damage associated with inflammation and fibrosis. However, the ability of activin A to sculpt the subsequent immune response as well means that the full range of effects that might arise from blocking activin bioactivity will need to be considered in any therapeutic applications.
激活素是转化生长因子-β超家族的成员，对细胞生长和分化具有广泛而复杂的影响。激活素 A 长期以来一直被认为是炎症和免疫的关键调节剂，而激活素 B 也具有类似的作用，它们具有 65%的序列同源性。这些分子及其结合蛋白卵泡抑素广泛表达，在许多急性和慢性炎症条件下其产量增加。激活素的合成和释放受炎症细胞因子、Toll 样受体配体和氧化应激的刺激。激活素与异二聚体丝氨酸/苏氨酸激酶受体复合物相互作用，激活 SMAD 转录因子和 MAP 激酶信号通路，从而介导炎症、应激和免疫。卵泡抑素与激活素具有高亲和力结合，从而阻断激活素受体结合位点，并将其靶向细胞表面蛋白聚糖和溶酶体降解。使用转基因小鼠和基因敲除小鼠的研究以及使用外源性卵泡抑素的阻断研究已经证实，激活素 A 在恶病质、败血症、结肠炎和哮喘等急性和慢性炎症反应以及纤维化的发生中起着关键作用。然而，激活素 A 也指导单核细胞/巨噬细胞、髓样树突状细胞和 T 细胞亚群的发育，以促进 2 型和调节性免疫反应。内源性和外源性卵泡抑素阻断激活素 A 的促炎和促纤维化作用的能力，导致人们对这种结合蛋白作为限制疾病严重程度和改善与炎症和纤维化相关的后续损伤的潜在治疗方法产生了兴趣。然而，激活素 A 塑造随后免疫反应的能力也意味着，在任何治疗应用中，都需要考虑阻断激活素生物活性可能产生的全部影响。
