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Stromal cell‐derived factor‐1/CXCR4 promotes IL‐6 production in human synovial fibroblasts
Author(s) -
Chen HsienTe,
Tsou HsiKai,
Hsu ChinJung,
Tsai ChunHao,
Kao ChengHsing,
Fong YiChin,
Tang ChihHsin
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23043
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , stromal cell , chemistry , microbiology and biotechnology , synovial fluid , stromal cell derived factor 1 , cytokine , cancer research , small interfering rna , chemokine , transfection , signal transduction , biology , cxcr4 , receptor , cell culture , immunology , medicine , osteoarthritis , biochemistry , pathology , alternative medicine , genetics
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.