Department of Medicine, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, USA.
Department of Internal Medicine, Division of Rheumatology and Clinical Immunogenetics, Houston, TX, USA.
Rheumatology (Oxford). 2018 Oct 1;57(10):1838-1850. doi: 10.1093/rheumatology/kex347.
SSc is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. IL-6 and related cytokines that signal through STAT3 have been implicated in the pathogenesis of SSc and mouse models of fibrosis. The aim of this study was to investigate the efficacy of inhibiting STAT3 in the development of fibrosis in two mouse models of skin fibrosis.
Biopsy samples of skin from SSc patients and healthy control subjects were used to determine the expression pattern of phosphotyrosyl (pY705)-STAT3. C188-9, a small molecule inhibitor of STAT3, was used to treat fibrosis in the bleomycin-induced fibrosis model and Tsk-1 mice. In vitro studies were performed to determine the extent to which STAT3 regulates the fibrotic phenotype of dermal fibroblasts.
Increased STAT3 and pY705-STAT3 was observed in SSc skin biopsies and in both mouse models of SSc. STAT3 inhibition with C188-9 resulted in attenuated skin fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of skin fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-β. Finally, TGF-β induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner.
STAT3 inhibition decreases dermal fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-β. These data suggest that STAT3 is a potential therapeutic target for dermal fibrosis in diseases such as SSc.
SSc 是一种自身免疫性疾病，其特征是皮肤和内脏器官进行性纤维化。通过 STAT3 信号传递的 IL-6 和相关细胞因子已被牵涉到 SSc 的发病机制和纤维化的小鼠模型中。本研究的目的是研究抑制 STAT3 在两种皮肤纤维化小鼠模型中纤维化发展中的疗效。
使用 SSc 患者和健康对照的皮肤活检样本来确定磷酸化酪氨酸（pY705）-STAT3 的表达模式。使用小分子 STAT3 抑制剂 C188-9 治疗博来霉素诱导的纤维化模型和 Tsk-1 小鼠中的纤维化。进行体外研究以确定 STAT3 在多大程度上调节真皮成纤维细胞的纤维化表型。
在 SSc 皮肤活检和两种 SSc 小鼠模型中均观察到 STAT3 和 pY705-STAT3 的增加。用 C188-9 抑制 STAT3 导致两种皮肤纤维化小鼠模型中的皮肤纤维化、肌成纤维细胞积累、促纤维化基因表达和胶原蛋白沉积减弱。C188-9 减少了由 IL-6 转信号诱导的体外真皮成纤维细胞产生的纤维化基因。最后，TGF-β以 SMAD3 依赖的方式诱导 STAT3 的磷酸化酪氨酸。
STAT3 抑制减少了两种 SSc 模型中的皮肤纤维化。STAT3 在体外调节真皮成纤维细胞的功能，并且可以被 TGF-β激活。这些数据表明 STAT3 是 SSc 等疾病中皮肤纤维化的潜在治疗靶标。
