title: Resveratrol inhibits BK-induced COX-2 transcription by suppressing acetylation of AP-1 and NF-κB in human rheumatoid arthritis synovial fibroblasts.
abstract: Bradykinin (BK) induces inflammation in rheumatoid arthritis (RA). Resveratrol is a potent activator of Sirt1 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/Sirt1 in human rheumatoid arthritis synovial fibroblasts (RASFs). We found that BK-induced COX-2 protein and mRNA expression associated with PGE2synthesis, and promoter activity was mediated through B2R receptors, which were attenuated by selective B2R antagonist Hoe140 or transfection with B2R siRNA. BK-induced responses were mediated through PKCμ, MAPKs, AP-1 and NF-κB which were inhibited by their respective inhibitors or siRNAs. Up-regulation of Sirt1 by resveratrol suppressed the BK-induced COX-2/PGE2production through inhibiting the interaction of AP-1 and NF-κB with COX-2 promoter in RASFs. BK-induced COX-2/PGE2expression is mediated through a B2R-PKCμ-dependent MAPKs, AP-1, and NF-κB 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.
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan. Electronic address: chuenmao@mail.cgu.edu.tw.
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chi
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
mesh_terms: D000107:Acetylation; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D001920:Bradykinin / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D043782:Receptor, Bradykinin B2; D013267:Stilbenes; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D015232:Dinoprostone; D000077185:Resveratrol; D001920:Bradykinin
keywords: Bradykinin; Cyclooxygenase-2; PKCμ; Resveratrol; Rheumatoid arthritis