Iguratimod Inhibits Skin Fibrosis by regulating TGF-β1/Smad Signaling Pathway in Systemic Sclerosis

Background: Iguratimod (T-614), exerting a powerful anti-inflammatory ability, has therapeutic efficacy in multiple autoimmune diseases. However, the effect of T614 on systemic sclerosis (SSc) is unclear. Here, we investigate the effect and molecular mechanism of T-614 in experimental SSc models.

Methods: In vitro, cultured dermal fibroblasts from four SSc patients were subjected to different doses of T-614 in the presence or absence of TGF-β1 stimulation. Cell proliferation, apoptosis, migration were determined by CCK-8,flow cytometry and transwell assay,respectively. Fibrosis markers and smad signaling pathway related proteins were detected by immunoblotting and immunofluorescence. In vivo, A bleomycin-induced SSc mouse model was used to evaluate the effect of T-614 on skin fibrosis. Pathological changes of skin tissues were evaluated by HE, Masson staining and immunohistochemistry.

Results: In the study, we found T614 inhibited TGF-β1-induced cell proliferation, migration and promoted apoptosis in a dose-dependent manner (all p < .01). T614 partially reversed TGF-β1-induced up-regulation of fibrosis markers and phosphorylation of smad2 and smad3 and blocked p-Smad3 nuclear translocation (all p < .05), suggesting T614 may inhibit dermal fibroblasts activation by regulating TGF-β/smad pathway. In vivo experiments, T-614 alleviated skin thickness in bleomycin-induced SSc mice (all p < .05). The expression of fibrosis markers and the infiltration of macrophages in skin tissue were significantly decreased after T614 treatment (all p < .05).

Conclusion: Our preliminary data indicated T614 inhibited dermal fibroblasts activation and skin fibrosis at least partly by regulating TGF-β1/smad pathway in experimental SSc models and may be a promising therapeutic agent for SSc.

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