The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells
The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells
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DOI：
10.1038/sj.ki.5000197
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发表时间：
2006-03-01
影响因子：
19.6
通讯作者：
Gruden, G
中科院分区：
文献类型：
--
作者：
Giunti, S;Pinach, S;Gruden, G
炎症和血流动力学因素都与糖尿病和其他进行性肾小球疾病的发病机制有关。机械拉伸可诱导系膜细胞表达细胞间黏附分子-1(ICAM-1)和单核细胞趋化蛋白-1(MCP-1)。CC趋化因子受体2(CCR2)是新近在人肾小球系膜细胞(HMCs)中发现的同源MCP-1受体。我们测试了MCP-1与CCR2结合是否影响HMCS中ICAM-1的表达，其次，拉伸诱导的ICAM-1是否由MCP-1通过自分泌机制介导。无血清的HMCs暴露于rh-MCP-1(0.1-1-10-50-100 ng/ml)或机械牵张(存在或不存在特异性CCR2抑制剂RS102895)。免疫荧光法和细胞荧光法检测ICAM-1的表达。黏附实验检测单核细胞与HMC的相互作用。用逆转录聚合酶链式反应、免疫印迹和流式细胞术检测CCR2的表达。Rh-MCP-1作用于HMCs后24 h，ICAM-1的表达显著增加一倍，导致单核细胞黏附增强。这种作用是通过CCR2受体实现的，因为CCR2在HMCS中表达，阻断CCR2可以阻止ICAM-1的上调。阻断CCR2不改变牵张诱导的ICAM-1表达，牵张通过MCP-1非依赖机制显著降低CCR2的mRNA和蛋白表达。综上所述，Stretch和MCP-1独立地诱导HMCS表达ICAM-1。牵张诱导的CCR2下调可能有利于MCP-1旁分泌活动。
Both inflammatory and haemodynamic factors have been implicated in the pathogenesis of diabetic and other progressive glomerulopathies. Mesangial cell exposure to mechanical stretch induces both intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression. CC Chemokine receptor 2 (CCR2), the cognate MCP-1 receptor, has been recently demonstrated in human mesangial cells (HMCs). We tested whether MCP-1 binding to CCR2 affects ICAM-1 expression in HMCs and, secondly, if stretch-induced ICAM-1 is mediated by MCP-1 via an autocrine mechanism. Serum-deprived HMCs were exposed to either rh-MCP-1 ( 0.1 - 1 - 10 - 50 - 100 ng/ml) or mechanical stretch in the presence and in the absence of RS102895, a specific CCR2 inhibitor. ICAM-1 expression was assessed both by immunofluorescence and cytofluorimetry. Monocyte - HMC interaction was tested by adhesion assay. CCR2 expression was studied by reverse transcriptase-polymerase chain reaction, immunoblotting, and flow cytometry. HMCs exposure to rh-MCP- 1 induced a significant twofold increase in ICAM-1 expression at 24 h, leading to enhanced monocyte adhesion. This effect occurred via the CCR2 receptor as CCR2 was expressed in HMCs and CCR2 blockade prevented ICAM-1 upregulation. Stretch-induced ICAM-1 expression was not altered by CCR2 blockade and stretch significantly reduced CCR2 mRNA and protein expression via an MCP-1-independent mechanism. In conclusion, stretch and MCP-1 independently induce ICAM-1 expression in HMCs. Stretch-induced CCR2 downregulation may favour MCP-1 paracrine activity.