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Among IL-17 families, IL-17A and IL-17F share amino acid sequence similarity and bind to IL-17R type A. IL-17 signaling is implicated in the pathogenesis of various autoimmune diseases, but its role in the regulatory mechanism of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) both remain to be elucidated. This study revealed that IL-17A expression was significantly increased in the involved skin and sera of SSc patients, whereas the IL-17F levels did not increase. In contrast, the expression of IL-17R type A in SSc fibroblasts significantly decreased in comparison with that in normal fibroblasts, due to the intrinsic TGF-ßl activation in these cell types. Moreover, IL-17A, not IL-17F, reduced the protein expression of al(I) collagen and connective tissue growth factor. miR-129-5p, one of the downregulated microRNAs in SSc fibroblasts, increased due to IL-17A and mediated the al(I) collagen reduction. These results suggest that IL-17A signaling, not IL-17F, has an antifibro-genic effect via the upregulation of miR-129-5p and the downregulation of connective tissue growth factor and al(I) collagen. IL-17A signaling is suppressed due to the downregulation of the receptor by the intrinsic activation of TGF-ßl in SSc fibroblasts, which may amplify the increased collagen accumulation and fibrosis characteristic of SSc. Increased IL-17A levels in the sera and involved skin of SSc may be due to negative feedback. Clarifying the novel regulatory mechanisms of fibrosis by the cytokine network consisting of TGF-ß and IL-17A may lead to a new therapeutic approach for this disease. [ABSTRACT FROM AUTHOR]

IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBB subunits, and EBB alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-p costimulation. We found that collagen mRNA stability was reduced by EBB via the induction of miR-4500. The IL-35 levels in the sera or on the surface of T cells were not altered in SSc patients, while EBB expression was decreased in the keratinocytes of the epidermis and regulatory T cells of the dermis in SSc skin compared with normal skin, which may induce collagen synthesis in SSc dermal fibroblasts. We also found that gpl30, the EBB receptor, was expressed in both normal and SSc fibroblasts. Moreover, we revealed that EBB supplementation by injection into the skin improves mice skin fibrosis. Decreased EBI3 in SSc skin may contribute to an increase in collagen accumulation and skin fibrosis. Clarifying the mechanism regulating the extracellular matrix expression by EBB in SSc skin may lead to better understanding of this disease and new therapeutic strategies using ointment or microinjection of the subunit. [ABSTRACT FROM AUTHOR]