LAUSR

HighlightsIL‐17 regulates Cyr61, IL‐23 and GM‐CSF expression by AA‐FLS via STAT‐3 signaling.Knockdown of IL‐17RA or inhibition of STAT‐3 activation abrogated these effects.IL‐17 enhanced the expression of IL‐17RA and SHP‐2 in AA‐FLS.IL‐17/IL‐17RA/STAT‐3 signaling cascade is crucial for RANKL production in AA‐FLS.This study provides a new insight into the pathogenesis of rheumatoid arthritis. &NA; Interleukin (IL)‐17 predominately produced by the Th17 cells, plays a crucial role in the fibroblast‐like synoviocytes (FLS) mediated disease process of rheumatoid arthritis (RA). IL‐17 exerts its pathogenic effects in RA‐FLS by IL‐17/IL‐17RA/STAT‐3 signaling. Recent studies have shown that RA‐FLS produces SHP‐2, Cyr61, IL‐23, GM‐CSF and RANKL which results in worsening of the disease. However, whether IL‐17/IL‐17RA/STAT‐3 signaling regulates SHP‐2, Cyr61, IL‐23, GM‐CSF and RANKL expressions in RA‐FLS remains unknown. In this study, IL‐17 treatment dramatically induced the production of Cyr61, IL‐23 and GM‐CSF in FLS isolated from adjuvant induced arthritis (AA) rats. Conversely, IL‐17 mediated production of Cyr61, IL‐23 and GM‐CSF was abrogated by knockdown of IL‐17RA using a small interfering RNA or blockade of STAT‐3 activation with S3I‐201 in AA‐FLS. Interestingly, IL‐17 treatment noticeably increased the expression of IL‐17RA and SHP‐2 in AA‐FLS. However, silencing of IL‐17RA reversed the effect of IL‐17 on the expression of IL‐17RA and SHP‐2 in AA‐FLS. In addition, an increased number of TRAP‐positive multinucleated cells were observed in a coculture system consisting of IL‐17 treated AA‐FLS and rat bone marrow derived monocytes/macrophages. Further, mechanistically we found that IL‐17 upregulated RANKL expression in AA‐FLS that was dependent on the IL‐17/IL‐17RA/STAT‐3 signaling cascade. Knockdown of IL‐17RA or inhibition of STAT‐3 activation decreased the IL‐ 17 induced RANKL expression by AA‐FLS and their osteoclastogenic potential. Taken together, our findings demonstrate that IL‐17 regulates SHP‐2 expression and IL‐17RA/STAT‐3 dependent production of Cyr61, IL‐23, GM‐CSF and RANKL in AA‐FLS and may reveal a new insight into the pathogenesis of RA.