Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway.
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.
Chiu
Yung-Cheng
YC
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Lin
Ching-Yuang
CY
Chen
Chao-Ping
CP
Huang
Kui-Chou
KC
Tong
Kwok-Man
KM
Tzeng
Chung-Yuh
CY
Lee
Tu-Sheng
TS
Hsu
Horng-Chaung
HC
Tang
Chih-Hsin
CH
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*
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