Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes - A regulatory role for plasma LDL
Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes - A regulatory role for plasma LDL
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DOI：
10.1161/01.atv.18.12.1983
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发表时间：
1998-12-01
影响因子：
8.7
通讯作者：
Quehenberger, O
中科院分区：
文献类型：
--
作者：
Han, KH;Tangirala, RK;Quehenberger, O
巨噬细胞源性泡沫细胞的内皮下积聚是动脉粥样硬化的标志之一。单核细胞向内膜的募集需要局部产生的趋化因子与特异性细胞表面受体的相互作用，包括单核细胞趋化蛋白-1的受体（CCR 2）。（MCP-1）。我们以前曾报道单核细胞CCR 2基因表达和功能被促炎细胞因子有效下调。在这项研究中，我们确定了低密度脂蛋白（LDL）作为一个积极的调节因子CCR 2的表达。与正常胆固醇血症对照组相比，高胆固醇血症患者的单核细胞CCR 2表达显著增加。类似地，人THP-1单核细胞与LDL孵育诱导CCR 2 mRNA和蛋白的快速增加。到24小时，细胞表面受体的数量增加了一倍，导致对MCP-1的趋化反应增加了3倍。天然LDL促进了CCR 2表达和趋化性的增加，而氧化LDL则没有。氧化LDL迅速下调CCR 2的表达，而还原甲基化LDL，它不结合LDL受体，只有温和的影响CCR 2的表达。一种中和性抗LDL受体抗体阻止了LDL的作用，表明LDL的结合和内化对于CCR 2的上调是必不可少的。CCR 2表达的诱导似乎是由LDL衍生的胆固醇介导的，因为用游离胆固醇处理的细胞也显示CCR 2表达增加。这些数据表明，在高胆固醇血症等条件下，血浆LDL水平升高可增强单核细胞CCR 2表达和趋化反应，并可能导致慢性炎症和动脉粥样硬化形成中单核细胞向血管壁募集增加。
The subendothelial accumulation of macrophage-derived foam cells is one of the hallmarks of atherosclerosis. The recruitment of monocytes to the intima requires the interaction of locally produced chemokines with specific cell surface receptors, including the receptor (CCR2) for monocyte chemoattractant protein-1. (MCP-1). We have previously reported that monocyte CCR2 gene expression and function are effectively downregulated by proinflammatory cytokines. In this study we identified low density lipoprotein (LDL) as a positive regulator of CCR2 expression. Monocyte CCR2 expression was dramatically increased in hypercholesterolemic patients compared with normocholesterolemic controls. Similarly, incubation of human THP-1 monocytes with LDL induced a rapid increase in CCR2 mRNA and protein. By 24 hours the number of cell surface receptors was doubled, causing a 3-fold increase in the chemotactic response to MCP-1. The increase in CCR2 expression and chemotaxis was promoted by native LDL but not by oxidized LDL. Oxidized LDL rapidly downregulated CCR2 expression, whereas reductively methylated LDL, which does not bind to the LDL receptor, had only modest effects on CCR2 expression. A neutralizing anti-LDL receptor antibody prevented the effect of LDL, suggesting that binding and internalization of LDL were essential for CCR2 upregulation. The induction of CCR2 expression appeared to be mediated by LDL-derived cholesterol, because cells treated with free cholesterol also showed increased CCR2 expression. These data suggest that elevated plasma LDL levels in conditions such as hypercholesterolemia enhance monocyte CCR2 expression and chemotactic response and potentially contribute to increased monocyte recruitment to the vessel wall in chronic inflammation and atherogenesis.