Interleukin 17 regulates SHP-2 and IL-17RA/STAT-3 dependent Cyr61, IL-23 and GM-CSF expression and RANKL mediated osteoclastogenesis by fibroblast-like synoviocytes in rheumatoid arthritis.

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.

Ganesan R ，Rasool M 《-》

Cyanidin prevents the hyperproliferative potential of fibroblast-like synoviocytes and disease progression via targeting IL-17A cytokine signalling in rheumatoid arthritis.

The hyperplastic phenotype of fibroblast-like synoviocytes (FLSs) plays an important role for synovitis, chronic inflammation and joint destruction in rheumatoid arthritis (RA). Interleukin 17A (IL-17A), a signature pro-inflammatory cytokine effectively influences the hyperplastic transformation of FLS cells and synovial pannus growth. IL-17A cytokine signalling participates in RA pathology by regulating an array of pro-inflammatory mediators and osteoclastogenesis. Cyanidin, a key flavonoid inhibits IL-17A/IL-17 receptor A (IL-17RA) interaction and alleviates progression and disease severity of psoriasis and asthma. However, the therapeutic efficacy of cyanidin on IL-17A cytokine signalling in RA remains unknown. In the present study, cyanidin inhibited IL-17A induced migratory and proliferative capacity of FLS cells derived from adjuvant-induced arthritis (AA) rats. Cyanidin treatment reduced IL-17A mediated reprogramming of AA-FLS cells to overexpress IL-17RA. In addition, significantly decreased expression of IL-17A dependent cyr61, IL-23, GM-CSF, and TLR3 were observed in AA-FLS cells in response to cyanidin. At the molecular level, cyanidin modulated IL-17/IL-17RA dependent JAK/STAT-3 signalling in AA-FLS cells. Importantly, cyanidin activated PIAS3 protein to suppress STAT-3 specific transcriptional activation in AA-FLS cells. Cyanidin treatment to AA rats attenuated clinical symptoms, synovial pannus growth, immune cell infiltration, and bone erosion. Cyanidin reduced serum level of IL-23 and GM-CSF and expression of Cyr 61 and TLR3 in the synovial tissue of AA rats. Notably, the level of p-STAT-3 protein was significantly decreased in the synovial tissue of AA rats treated with cyanidin. This study provides the first evidence that cyanidin can be used as IL-17/17RA signalling targeting therapeutic drug for the treatment of RA and this need to be investigated in RA patients.

Samarpita S ，Ganesan R ，Rasool M 《-》

Ferulic acid inhibits interleukin 17-dependent expression of nodal pathogenic mediators in fibroblast-like synoviocytes of rheumatoid arthritis.

Interleukin 17 (IL-17), a proinflammatory cytokine produced by T helper (Th) 17 cells, potentially controls fibroblast-like synoviocytes (FLS)-mediated disease activity of rheumatoid arthritis (RA) via IL-17/ IL-17 receptor type A (IL-17RA)/signal transducer and activator of transcription 3 (STAT-3) signaling cascade. This has suggested that targeting IL-17 signaling could serve as an important strategy to treat FLS-mediated RA progression. Ferulic acid (FA), a key polyphenol, attenuates the development of gouty arthritis and cancer through its anti-inflammatory effects, but its therapeutic efficiency on IL-17 signaling in FLS-mediated RA pathogenesis remains unknown. In the current study, FA markedly inhibited the IL-17-mediated expression of its specific transmembrane receptor IL-17RA in FLS isolated from adjuvant-induced arthritis (AA) rats. Importantly, FA dramatically suppressed the IL-17-mediated expression of toll-like receptor 3 (TLR-3), cysteine-rich angiogenic inducer 61 (Cyr61), IL-23, granulocyte-macrophage colony stimulating factor (GM-CSF) in AA-FLS via the inhibition of IL-17/IL-17RA/STAT-3 signaling cascade. In addition, FA significantly decreased the formation of osteoclast cells and bone resorption potential in a coculture system consisting of IL-17 treated AA-FLS and rat bone marrow derived monocytes/macrophages. Furthermore, FA remarkably inhibited the IL-17-mediated expression of receptor activator of nuclear factor κ-Β ligand (RANKL) and increased the expression of osteoprotegerin (OPG) in AA-FLS via the regulation of IL-17/IL-17RA/STAT-3 signaling cascade. The therapeutic efficiency of FA on IL-17 signaling was further confirmed by knockdown of IL-17RA using small interfering RNA or blocking of STAT-3 activation with S3I-201. The molecular docking analysis revealed that FA manifests significant ligand efficiency toward IL-17RA, STAT-3, IL-23, and RANKL proteins. This study provides new evidence that FA can be used as a potential therapeutic agent for inhibiting IL-17-mediated disease severity and bone erosion in RA.

Ganesan R ，Rasool M 《-》

Cyr61 induces IL-6 production by fibroblast-like synoviocytes promoting Th17 differentiation in rheumatoid arthritis.

Lin J ，Zhou Z ，Huo R ，Xiao L ，Ouyang G ，Wang L ，Sun Y ，Shen B ，Li D ，Li N ... -  《-》

IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-kappaB signal pathways.

Li X ，Kim KW ，Cho ML ，Ju JH ，Kang CM ，Oh HJ ，Min JK ，Lee SH ，Park SH ，Kim HY ... -  《-》