T-Cell Proapoptotic and Antifibrotic Activity Against Autologous Skin Fibroblasts Is Associated With IL-17A Axis Upregulation in Systemic Sclerosis.

Systemic sclerosis (SSc) T cells can induce apoptosis of autologous skin fibroblasts . Th17 cells have been reported to increase in SSc patients, and interleukin-17A (IL-17A) has a profibrotic function. We used a system based on T-cell-autologous fibroblast co-cultures to further investigate a possible role of IL-17A in SSc. T cells from diffuse SSc patients were co-cultured with autologous skin fibroblasts. mRNA was assessed by real-time PCR in co-cultured and control T cells, while , and mRNAs were assessed in co-cultured and control fibroblasts. In subset experiments, co-cultures and control cells were treated with either IL-17A or IL-17A anti-IL17 receptor monoclonal antibody (α-IL-17RA mAb). Chemokine and procollagen type I (PCI) production was further investigated at the protein level in cell culture supernatants by multiple suspension immunoassay and sandwich ELISA, respectively. Co-cultured and control fibroblasts were also stained with Annexin V and analyzed by flow cytometry. T cell-fibroblast co-cultures overexpressed and . Furthermore, co-cultured fibroblasts upregulated IL-17A targets , and , while , and two key effectors of the TGF-β signaling, and , were found downregulated. Consistently, chemokine concentrations were increased in co-culture supernatants, while PCI levels were reduced, especially after stimulation with ectopic IL-17A. Finally, simultaneous α-IL-17RA mAb treatment restored PCI levels and reduced fibroblast apoptosis in IL-17A-stimulated co-cultures. These data suggest that IL-17A upregulation might play a role in modulating T cell-mediated antifibrotic and proapoptotic effects in co-cultured autologous skin fibroblasts.