title: Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway.
abstract: Peptidoglycan (PGN), the major component of the cell wall of Gram-positive bacteria, activates the innate immune system of the host and induces the release of cytokines and chemokines. We investigated the signaling pathway involved in IL-6 production stimulated by PGN in rheumatoid arthritis synovial fibroblasts. PGN caused concentration- and time-dependent increases in IL-6 production. PGN-mediated IL-6 production was attenuated by TLR2 small interfering RNA and nucleotide-binding oligomerization domain 2 small interfering RNA. Pretreatment with PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor, and AP-1 inhibitor (tanshinone IIA) also inhibited the potentiating action of PGN. PGN increased the focal adhesion kinase (FAK), PI3K, and Akt phosphorylation. Stimulation of rheumatoid arthritis synovial fibroblast cells with PGN increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the IL-6 promoter. PGN mediated an increase in the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to AP-1 element was inhibited by Ly294002, Akt inhibitor, and FAK mutant. Our results suggest that PGN increased IL-6 production in human synovial fibroblasts via the TLR2 receptor/FAK/PI3K/Akt and AP-1 signaling pathway.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yung-Cheng
authors.initials: YC
authors.lastname: Chiu
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.forename: Chao-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Kui-Chou
authors.initials: KC
authors.lastname: Huang
authors.forename: Kwok-Man
authors.initials: KM
authors.lastname: Tong
authors.forename: Chung-Yuh
authors.initials: CY
authors.lastname: Tzeng
authors.forename: Tu-Sheng
authors.initials: TS
authors.lastname: Lee
authors.forename: Horng-Chaung
authors.initials: HC
authors.lastname: Hsu
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D010457:Peptidoglycan; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt