title: HMGB-1 induces IL-6 production in human synovial fibroblasts through c-Src, Akt and NF-κB pathways.
abstract: High mobility group box chromosomal protein 1 (HMGB-1) is a widely studied, ubiquitous nuclear protein that is present in eukaryotic cells, and plays a crucial role in inflammatory response. However, the effects of HMGB-1 on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in HMGB-1-induced IL-6 production in human synovial fibroblast cells. HMGB-1 caused concentration- and time-dependent increases in IL-6 production. HMGB-1-mediated IL-6 production was attenuated by receptor for advanced glycation end products (RAGE) monoclonal antibody (Ab) or siRNA. Pretreatment with c-Src inhibitor (PP2), Akt inhibitor and NF-κB inhibitor (pyrrolidine dithiocarbamate and L-1-tosylamido-2-phenylenylethyl chloromethyl ketone) also inhibited the potentiating action of HMGB-1. Stimulation of cells with HMGB-1 increased the c-Src and Akt phosphorylation. HMGB-1 increased the accumulation of p-p65 in the nucleus, as well as NF-κB luciferase activity. HMGB-1-mediated increase of NF-κB luciferase activity was inhibited by RAGE Ab, PP2 and Akt inhibitor or RAGE siRNA, or c-Src and Akt mutant. Our results suggest that HMGB-1-increased IL-6 production in human synovial fibroblasts via the RAGE receptor, c-Src, Akt, p65, and NF-κB signaling pathways.
authors.affiliation: Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Hou
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013583:Synovial Membrane / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D024243:HMGB1 Protein; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D011743:Pyrimidines; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt