title: Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-beta in fibroblast like synoviocytes of patients with RA.
abstract: Cytokine and chemokine receptors play a key role in inflammation caused by rheumatoid arthritis (RA). Two isoforms of human CC chemokine receptor R2 (CCR2), the receptor of monocyte chemoattractant protein 1 (MCP-1), have been identified but their relative expression in fibroblast-like synoviocytes (FLS) and their contribution to inflammatory responses mediated by MCP-1 or inflammatory cytokines in patients with RA remain uncertain. We examined the pattern of expression of two CCR2 isoforms upon stimulation by proinflammatory cytokines and CD40 ligation. FLS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1beta, IL-18, IL-15, and LPS. CCR2A and CCR2B expression was examined by immunohistochemistry, RT-PCR and western blot analysis. IL-15, TNF-alpha and MCP-1 production was determined by ELISA. Immunohistochemistry showed that CCR2A is highly expressed in RA synovium compared with OA synovium. Transcripts of both CCR2A and CCR2B were detected in FLS. Exogenous MCP-1, CD40L, TGF-beta, and IL-15 significantly increased the expression of CCR2A but not CCR2B. Exposure of FLS to sCD40L caused strong upregulation of CCR2A but not of CCR2B protein expression. MCP-1 increased the proliferation of FLS and the production of IL-15, TNF-alpha, and IL-18. Because CCR2A is the main target of regulation by cytokines and CD40 ligation, the relatively higher expression of CCR2A on the cell surface suggests that this isoform of MCP-1 receptor functions as the principal mediator of inflammatory signals in RA FLS.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, The Center for Rheumatic Diseases, The Rheumatism Research Center, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Yoon
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Young Ok
authors.initials: YO
authors.lastname: Jung
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D018925:Chemokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D020033:Protein Isoforms; D054390:Receptors, CCR2 / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D020033:Protein Isoforms; D054390:Receptors, CCR2; D016212:Transforming Growth Factor beta; D023201:CD40 Ligand