title: Stromal cell-derived factor-1/CXCR4 promotes IL-6 production in human synovial fibroblasts.
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.
authors.affiliation: Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Hsien-Te
authors.initials: HT
authors.lastname: Chen
authors.forename: Hsi-Kai
authors.initials: HK
authors.lastname: Tsou
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.forename: Cheng-Hsing
authors.initials: CH
authors.lastname: Kao
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D001596:Benzylamines; D015153:Blotting, Western; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology*; D000080027:Cyclams; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; D018808:Transcription Factor AP-1; C088327:plerixafor