title: Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cdelta and NF-kappaB pathway in human synovial fibroblasts.
abstract: Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. It has been shown to induce interleukin-6 (IL-6) expression in inflammatory responses in rheumatoid arthritis. We investigated the signaling pathway involved in IL-6 production caused by BK in synovial fibroblasts. BK caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or genetic inhibition of the BK receptor, siRNA revealed that B2 but not B1 BK receptors are involved in BK-mediated up-regulation of IL-6. BK-mediated IL-6 production was attenuated by phospholipase C inhibitor (U73122), protein kinase Cdelta inhibitor (rottlerin), NF-kappaB inhibitor (PDTC), IkappaB protease inhibitor (TPCK) and NF-kappaB inhibitor peptide. Stimulation of synovial fibroblasts with BK activated IkappaB kinase alpha/beta (IKK alpha/beta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus and kappaB-luciferase activity. BK mediated an increase of IKK alpha/beta and IkappaBalpha phosphorylation, kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by B2 BK receptor antagonist (HOE140), U73122 and rottlerin. Our results suggest that BK increased IL-6 production in synovial fibroblasts via the B2 BK receptor/PI-PLC/PKCdelta/and NF-kappaB signaling pathway.
authors.affiliation: Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Cheng-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Dong-Chen
authors.initials: DC
authors.lastname: Shieh
authors.forename: Chung-Yuh
authors.initials: CY
authors.lastname: Tzeng
authors.forename: Chao-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Shun-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Yung-Cheng
authors.initials: YC
authors.lastname: Chiu
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D001920:Bradykinin / Q000494:pharmacology*; D065094:Bradykinin B2 Receptor Antagonists; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis*; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D051996:Transcription Factor RelA; D008156:Luciferases; D051550:I-kappa B Kinase; D051745:Protein Kinase C-delta; D010738:Type C Phospholipases; D001920:Bradykinin