Lin Chi Iou, Chen Chiung-Nien, Chen Jiun Hong, Lee Hsinyu
Institute of Zoology, National Taiwan University, Taipei, Taiwan.
J Cell Biochem. 2006 Nov 1;99(4):1216-32. doi: 10.1002/jcb.20963.
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both low-molecular-weight lysophospholipid (LPL) ligands which are recognized by the Edg family of G protein-coupled receptors (GPCRs). In endothelial cells, these two ligands activate Edg receptors resulting in cell proliferation and cell migration. Interleukin-8 (IL-8) is a C-X-C chemokine and acts as a chemoattractant of neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine and functions mainly as a chemoattractant of monocytes/macrophages. Both factors are secreted from endothelial cells and have been implicated in the processes leading to atherosclerosis. We examined the effects of LPLs on the expression of IL-8 and MCP-1, key regulators of leukocyte recruitment in human umbilical cord vein endothelial cells (HUVECs). Work illustrated in this article showed that LPA and S1P enhanced IL-8 and MCP-1 mRNA expressions, and protein secretions in dose- and time-dependent fashions. Maximal mRNA expression appeared at 16 hr post-ligand treatment. Using prior treatments with chemical inhibitors, LPLs enhanced IL-8 and MCP-1 expressions through a Gi-, Rho-, and NFkappaB-dependent mechanism. In a chemotaxis assay system, LPL treatments of endothelial cells enhanced monocyte recruitment through upregulating IL-8 and MCP-1 protein secretions. Pre-incubation with AF12198, an IL-1 receptor antagonist or IL-1 functional blocking antibody both suppressed the enhanced effects elicited by LPLs of IL-8 and MCP-1 mRNA expressions in HUVECs. These results suggest that LPLs released by activated platelets might enhance the IL-8- and MCP-1-dependent chemoattraction of monocytes toward the endothelium through an IL-1-dependent mechanism, which may play an important role in facilitating wound-healing and inflammation processes.
溶血磷脂酸（LPA）和1-磷酸鞘氨醇（S1P）均为低分子量溶血磷脂（LPL）配体，可被G蛋白偶联受体（GPCR）的Edg家族识别。在内皮细胞中，这两种配体激活Edg受体，导致细胞增殖和细胞迁移。白细胞介素-8（IL-8）是一种C-X-C趋化因子，作为中性粒细胞的趋化因子，而单核细胞趋化蛋白-1（MCP-1）是一种C-C趋化因子，主要作为单核细胞/巨噬细胞的趋化因子。这两种因子均由内皮细胞分泌，并与动脉粥样硬化的发生过程有关。我们研究了LPLs对人脐静脉内皮细胞（HUVECs）中白细胞募集的关键调节因子IL-8和MCP-1表达的影响。本文所示的研究表明，LPA和S1P以剂量和时间依赖性方式增强IL-8和MCP-1的mRNA表达及蛋白分泌。配体处理后16小时出现最大mRNA表达。使用化学抑制剂进行预处理，LPLs通过Gi、Rho和NFκB依赖性机制增强IL-8和MCP-1的表达。在趋化分析系统中，LPLs处理内皮细胞通过上调IL-8和MCP-1蛋白分泌增强单核细胞募集。用IL-1受体拮抗剂AF12198或IL-1功能阻断抗体预孵育均抑制了LPLs对HUVECs中IL-8和MCP-1 mRNA表达的增强作用。这些结果表明，活化血小板释放的LPLs可能通过IL-1依赖性机制增强单核细胞对内皮的IL-8和MCP-1依赖性趋化作用，这可能在促进伤口愈合和炎症过程中起重要作用。
