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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0802826v1 183/4/2785    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chiu, Y.-C. Articles by Tang, C.-H. PubMed PubMed Citation Articles by Chiu, Y.-C. Articles by Tang, C.-H.

Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1- Dependent Pathway¹

Yung-Cheng Chiu^*,,¶, Ching-Yuang Lin^*, Chao-Ping Chen, Kui-Chou Huang, Kwok-Man Tong, Chung-Yuh Tzeng, Tu-Sheng Lee, Horng-Chaung Hsu^2,* and Chih-Hsin Tang^2,,

^* Graduate Institute of Clinical Medical Science, Department of Pharmacology, and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan; and ^¶ Department of Nursing, Hungkuang University, Taichung, Taiwan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Science Council of Taiwan (96-2320-B-039-028-MY3 and 97-2320-B-039-31-MY3) and Taichung Veterans General Hospital (TCVGH-985102B and 985103C).

² Address correspondence and reprint requests to Dr. Horng-Chaung Hsu, Graduate Institute of Clinical Medical Science and Dr. Chih-Hsin Tang, Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan. E-mail addresses: d4749{at}mail.cmuh.org.tw and chtang{at}mail.cmu.edu.tw

³ Abbreviations used in this paper: RA, rheumatoid arthritis; PGN, peptidoglycan; siRNA, small interference RNA; RASF, RA synovial fibroblasts; FAK, focal adhesion kinase; ODN, oligonucleotide; AS, antisense; MS, missense; LF2000, Lipofectamine 2000; NOD2, nucleotide-binding oligomerization.