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Adiponectin Enhances IL-6 Production in Human Synovial Fibroblast via an AdipoR1 Receptor, AMPK, p38, and NF-B Pathway¹

Chih-Hsin Tang^2,*, Yung-Cheng Chiu, Tzu-Wei Tan^*, Rong-Sen Yang^2, and Wen-Mei Fu^2,

^* Department of Pharmacology, College of Medicine, China Medical University, Taichung, Taiwan; Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan; and Department of Orthopaedics and Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

Articular adipose tissue is a ubiquitous component of human joints, and adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and involved in energy homeostasis. We investigated the signaling pathway involved in IL-6 production caused by adiponectin in both rheumatoid arthritis synovial fibroblasts and osteoarthritis synovial fibroblasts. Rheumatoid arthritis synovial fibroblasts and osteoarthritis synovial fibroblasts expressed the AdipoR1 and AdipoR2 isoforms of the adiponectin receptor. Adiponectin caused concentration- and time-dependent increases in IL-6 production. Adiponectin-mediated IL-6 production was attenuated by AdipoR1 and 5'-AMP-activated protein kinase (AMPK)1 small interference RNA. Pretreatment with AMPK inhibitor (araA and compound C), p38 inhibitor (SB203580), NF-B inhibitor, IB protease inhibitor, and NF-B inhibitor peptide also inhibited the potentiating action of adiponectin. Adiponectin increased the kinase activity and phosphorylation of AMPK and p38. Stimulation of synovial fibroblasts with adiponectin activated IB kinase / (IKK /), IB phosphorylation, IB degradation, p65 phosphorylation at Ser (276), p65 and p50 translocation from the cytosol to the nucleus, and B-luciferase activity. Adiponectin-mediated an increase of IKK / activity, B-luciferase activity, and p65 and p50 binding to the NF-B element and was inhibited by compound C, SB203580 and AdipoR1 small interference RNA. Our results suggest that adiponectin increased IL-6 production in synovial fibroblasts via the AdipoR1 receptor/AMPK/p38/IKK and NF-B 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 National Science Council of Taiwan (NSC 95-2314-B-039-045) and China Medical University (CMU 95-208, 95-309, and 95-PH-06).

² Address correspondence and reprint requests to Dr. Tang Chih-Hsin, Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan; Yang Rong-Sen, Department of Orthopaedics, National Taiwan University and Hospital, Taiwan; or Fu Wen-Mei, Department of Pharmacology, College of Medicine, National Taiwan University, Taiwan. E-mail addresses: chtang{at}mail.cmu.edu.tw, rsyang{at}ntuh.gov.tw, or wenmei{at}ntu.edu.tw

³ Abbreviations used in this paper: OA, osteoarthritis; siRNA, small interference RNA; IKK, IB kinase; LPS, Lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; RT-PCR, reverse transcriptase-polymerase chain reaction; DAPA, DNA affinity protin-binding assay; ChIP, chromatin immunoprecipitation assay; RA, rheumatoid arthritis; AMPK, 5'-AMP-activated protein kinase; RASF, rheumatoid arthritis synovial fibroblasts; OASF, osteoarthritis synovial fibroblasts.