Stromal cell-derived factor-1/CXCR4 promotes IL-6 production in human synovial fibroblasts

✍ Scribed by Hsien-Te Chen; Hsi-Kai Tsou; Chin-Jung Hsu; Chun-Hao Tsai; Cheng-Hsing Kao; Yi-Chin Fong; Chih-Hsin Tang

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 729 KB
• Volume: 112
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.23043

✦ Synopsis

Abstract

The production of chemokine stromal cell‐derived factor (SDF)‐1 is significantly higher in synovial fluid of patients with osteoarthritis (OA). IL‐6 is a multifunctional cytokine that plays a central role in both OA and rheumatoid arthritis. However, the effects of SDF‐1α on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in SDF‐1α‐induced IL‐6 production in human synovial fibroblast cells. SDF‐1α caused concentration‐ and time‐dependent increases in IL‐6 production. SDF‐1α also increased the mRNA and surface expression of CXCR4 receptor in human synovial fibroblasts. CXCR4‐neutralizing antibody, CXCR4‐specific inhibitor (AMD3100), or small interfering RNA against CXCR4 inhibited the SDF‐1α‐induced increase of IL‐6 expression. The transcriptional regulation of IL‐6 by SDF‐1α was mediated by phosphorylation of phosphatidylinositol 3‐kinase (PI3K)/Akt and activation of the activator protein (AP)‐1 component of c‐Jun. The binding of c‐Jun to the AP‐1 element on the IL‐6 promoter and the increase in AP‐1 luciferase activity was enhanced by SDF‐1α. Co‐transfection with CXCR4, PI3K, Akt, and c‐Jun mutants or siRNA inhibited the potentiating action of SDF‐1α on AP‐1 promoter activity. Taken together, our results suggest that SDF‐1α‐increased IL‐6 production in human synovial fibroblasts via the CXCR4 receptor, PI3K, Akt, c‐Jun, and AP‐1 signaling pathways. J. Cell. Biochem. 112: 1219–1227, 2011. © 2011 Wiley‐Liss, Inc.