Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-β in fibroblast like synoviocytes of patients with RA
Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-β in fibroblast like synoviocytes of patients with RA
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DOI：
10.1038/emm.2007.55
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发表时间：
2007-08-31
影响因子：
12.8
通讯作者：
Kim, Flo-Youn
中科院分区：
文献类型：
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作者：
Cho, Mi-La;Yoon, Bo-Young;Kim, Flo-Youn
细胞因子和趋化因子受体在类风湿性关节炎（RA）引起的炎症中起关键作用。人类CC趋化因子受体R2 (CCR2)，单核细胞趋化蛋白1 （MCP-1）的受体，已经确定了两种同种异构体，但它们在成纤维细胞样滑膜细胞（FLS）中的相对表达以及它们在RA患者中由MCP-1或炎症细胞因子介导的炎症反应中的作用仍不确定。我们研究了促炎细胞因子和CD40连接刺激下两种CCR2亚型的表达模式。从RA患者的滑膜组织中制备FILS，并在MCP-1、可溶性CD40配体（sCD40L）、tgf - β、IL-1 β、IL-18、IL-15和LPS的存在下培养。免疫组织化学、RT-PCR和western blot检测CCR2A和CCR2B的表达。ELISA法检测IL-15、tnf - α和MCP-1的产生。免疫组化结果显示，CCR2A在RA滑膜中的表达高于OA滑膜。在FILS中检测到CCR2A和CCR2B的转录本。外源性MCP-1、CD40L、tgf - β和IL-15显著增加CCR2A的表达，但不增加CCR2B的表达。FLS暴露于sCD40L后，CCR2A蛋白表达明显上调，但CCR2B蛋白表达不明显。MCP-1增加了FLS的增殖和IL-15、tnf - α和IL-18的产生。由于CCR2A是细胞因子和CD40连接调节的主要靶点，CCR2A在细胞表面相对较高的表达表明，这种MCP-1受体亚型在RA FILS中是炎症信号的主要介质。
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. FILS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1 beta, 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 FILS. 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 FILS.