Transforming growth factor–β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2–anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.

转化生长因子-β (TGFβ) 是纤维发生的关键驱动因素。哺乳动物中的三种 TGFβ 亚型（TGFβ1、TGFβ2 和 TGFβ3）在胚胎发育中具有不同的功能；然而，TGFβ2和TGFβ3的产后病理作用和激活机制尚未得到很好的表征。在这里，我们表明潜在形式的 TGFβ2 和 TGFβ3 可以通过不依赖整合素的机制激活，并且与 TGFβ1 相比具有更低的激活阈值。与TGFB1、TGFB2和TGFB3不同与健康对照组织相比，人肺和肝纤维化组织中的表达增加。因此，TGFβ2和TGFβ3可能在纤维化中起病理作用。诱导型条件性敲除小鼠和抗 TGFβ 异构体选择性抗体证明 TGFβ2 和 TGFβ3 独立参与体内小鼠纤维化模型，选择性 TGFβ2 和 TGFβ3 抑制不会导致泛 TGFβ 异构体抑制观察到的炎症增加。TGFβ2-抗 TGFβ2/3 抗体复合物的共晶体结构揭示了变构异构体选择性抑制机制。因此，抑制 TGFβ2 和/或 TGFβ3 而保留 TGFβ1 可以缓解纤维化，而没有与泛 TGFβ 阻断相关的毒性问题。