Abstract: Abstract: Objective To investigate the molecular mechanisms of upregulated expression of cellular Fas-associated death domain-like interleukin-1 beta converting enzyme inhibitory protein (c-FLIP) by calreticulin (CRT) in patients with rheumatoid arthritis (RA). Methods The semi-quantitative analysis and localization of c-FLIP in RA and osteoarthritis (OA) synovium were detected by immunohistochemistry. The fibroblast-like synoviocytes (FLS) were isolated by enzymatic digestion of synovial tissue specimens obtained from RA and OA patients, and cultured as an in vitro experiment model. The expressions of c-FLIP in RA and OA synovial fibroblasts were detected by immunofluorescence and Western blot assay. Whether CRT influenced c-FLIP expression and its molecular mechanism were explored by Western blot assay. Results The high expression of c-FLIP was found in RA synovium, mainly in the lining and sublining areas of FLS and vascular endothelial cells detected by immunohistochemistry. Meanwhile, weak staining of c-FLIP was observed in OA synovium. The expression of c-FLIP was significantly higher in RA synovium than that of OA synovium (t=11.717, P＜0.001). Results of immunofluorescence and Western blot assay showed that c-FLIP was mainly located in cytoplasm, and which was higher expressed in FLS of RA than that of OA. The increased c-FLIP expression and phosphorylation of NF- κB were detected after being co-incubated with exogenous CRT (0, 10, 50, 100 μg / L), in dose-dependent manner. The effect of CRT upregulating c-FLIP expression was blocked by NF-κB inhibitor BAY 11-7082. Conclusion CRT can increase c-FLIP expression at least partly through NF-κB pathway in RA, which may provide therapeutic target for the treatment of RA.

Key words: Key words: calreticulin, arthritis, rheumatoid, NF-kappa B, c-FLIP