Bradykinin (BK) induces inflammation in rheumatoid arthritis (RA). Resveratrol is a potent activator of Sirtl which could modulate inflammation through deacetylating histones of transcription factors. Here, we investigated the mechanisms underlying BK-induced COX-2 expression which is modulated by resveratrol/Sirtl in human rheumatoid arthritis synovial fibroblasts (RASFs). We found that BI( induced COX-2 protein and mRNA expression associated with PGE(2) synthesis, and promoter activity was mediated through B2R receptors, which were attenuated by selective B2R antagonist Hoel 40 or transfection with B2R siRNA. BI(-induced responses were mediated through PKC mu, MAPKs, AP-1 and NF-kappa B which were inhibited by their respective inhibitors or siRNAs. Up-regulation of Sirtl by resveratrol suppressed the BK-induced COX-2/PGE(2) production through inhibiting the interaction of AP-1 and NF-kappa B with COX-2 promoter in RASF5. BK-induced COX-2/PGE(2) expression is mediated through a B2R-PKC mu-dependent MAPKs, AP-1, and NF-kappa B cascade. Resveratrol inhibited the phosphorylation and acetylation of p65, c-Jun, and Fos and reduced the binding to the COX-2 promoter, thereby attenuated the COX-2 expression. Therefore, resveratrol may be a promising therapeutic intervention for treatment of inflammatory arthritis. (C) 2017 Elsevier Inc. All rights reserved.