A novel pathogenic mechanism of the ER chaperone BiP/Grp78 response in rheumatoid synoviocytes (137.27)

Abstract

Abstract The accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we investigated the role of the ER chaperone BiP/Grp78 in abnormal proliferation of rheumatoid arthritis (RA) synoviocytes, which is the pathologic hallmark of RA. The results showed that BiP protein was highly expressed in RA synovium and synoviocytes. The proinflammatory cytokines, such as TNF-alpha and IL-1beta, and hypoxic stimuli, but not IL-10, increased the BiP expression in RA synoviocytes. RA synoviocytes were more resistant to ER-stress-induced apoptosis as compared to OA synoviocytes. ER stress inducers, thapsigargin and tunicamycin, increased BiP and Bcl-2 expressions in synoviocytes, which were much greater in RA synoviocytes than in OA synoviocytes. A BiP-inducer, BIX, blocked the ER-stress induced synoviocyte apoptosis, possibly by increasing Bcl-2 and BiP expression. In contrast, BiP knockdown in RA synoviocytes, using siRNA, abolished the TNF-alpha- and TGF-beta-induced synoviocyte proliferation and cyclin D1 upregulation. BiP with a higher molecular size than intracellular BiP was found in all (6/6) RA synovial fluids tested. Exogenous BiP strongly increased IL-17 and TNF-alpha production from RA mononuclear cells, but not from mononuclear cells of healthy controls. In summary, we demonstrated first that BiP is crucial to the resistance to apoptosis of RA synoviocytes and synoviocyte proliferation, and it involves the production of IL-17 and TNF-alpha from mononuclear cells, suggesting that ER chaperone BiP response contributes to RA pathogenesis by inducing synovial hyperplasia and Th17 cell generation.