Systemic sclerosis (SSc) is a connective tissue disease characterized by autoimmunity, vasculopathy, and fibrosis. Several studies demonstrated the involvement of various cytokines including IL-1 in SSc. IL-36 cytokines, a subgroup of IL-1 family, comprise IL-36α, β, γ, IL-36Ra, and IL-38. IL-36α, β, γ are known to promote inflammatory response, which is mainly produced by epithelial cells. Whereas, IL-36Ra as well as IL-38 may have anti-inflammatory effect. Recent reports suggest that epidermis may play an important role in the pathogenesis of SSc, although the involvement of IL-36 family is still unclear. Thus, we focused on IL-36 family regarding its level and function in SSc. IL-36α, β, γ and IL-38 expressions were evaluated by immunohistochemistry in skin tissue from SSc patients and healthy controls, and for IL-36γ by western blot analysis. Serum IL-36γ levels were evaluated by ELISA in 61 patients with SSc and controls. As results, IL-36γ expression levels were significantly higher in epidermis of SSc patients compared to that in controls and sera of SSc patients also had increased levels of IL-36γ. To analyze a role of IL-36γ in SSc, cultured healthy keratinocytes were stimulated with IL-36γ, and expression levels of epithelial-mesenchymal transition (EMT)-related factors were analyzed by qRT-PCR and Immunofluorescence. Expression levels of E-cadherin were significantly downregulated while that of Slug and Vimentin were increased in IL-36γ-stimulated keratinocytes with or without TGFβ than that in controls. Furthermore, skin fibroblasts in the presence of IL-36γ significantly induced Egr-1 expression. In conclusion, increased levels of IL-36γ in epidermis may be involved in the fibrotic pathogenesis of SSc by inducing EMT.
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