Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes
Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes
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DOI：
10.1182/blood-2002-09-2773
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Uguccioni, M
中科院分区：
文献类型：
--
作者：
Ogilvie, P;Paoletti, S;Uguccioni, M
Eotaxin-3 （CCL26）属于CC趋化因子组，可吸引嗜酸性粒细胞、嗜碱性粒细胞和Th2淋巴细胞。与eotaxin （CCL11）和eotaxin-2 （CCL24）一样，eotaxin-3通过CCR3介导其活性。在这里，我们发现eotaxin-3也能在单核细胞和CCR2转染的细胞上与CCR2结合。与单核细胞趋化蛋白1 （MCP-1; CCL2）相反，eotaxin-3不会触发细胞内钙动员、酶释放或丝裂原活化蛋白（MAP）激酶ERK的磷酸化，并在单核细胞中诱导弱趋化性。相反，eotaxin-3抑制mcp -1介导的反应，从而作为CCR2的天然拮抗剂。该研究还表明，在体外，eotaxin-3促进单核细胞远离eotaxin-3梯度的积极运动。当施加额外的MCP-1梯度时，这种驱避效果被放大，表明这两种机制是协同的。Eotaxin-3对单核细胞的影响；像MCP-1介导的迁移一样，排斥力对百日咳杆菌毒素敏感，表明G(i)蛋白偶联受体的参与。然而，使用表达CCR2的转染细胞，我们无法检测到F-actin的形成或eotaxin-3诱导的主动移动，这表明单一受体类型的表达不足以介导细胞排斥，或者使用的转染细胞系缺乏反向迁移所需的额外相互作用分子。Eotaxin-3在血管内皮细胞中表达，对嗜酸性粒细胞的内皮迁移至关重要。我们的数据提供了一种机制，通过这种机制，两个方向相反的趋化因子梯度可以有效地将单核细胞从血管驱逐到组织中。
Eotaxin-3 (CCL26) belongs to the group of CC chemokines that attract eosinophils, basophils, and Th2 lymphocytes. Like eotaxin (CCL11) and eotaxin-2 (CCL24), eotaxin-3 mediates its activity through CCR3. Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells. In contrast to monocyte chemotactic protein 1 (MCP-1; CCL2), eotaxin-3 does not trigger intracellular calcium mobilization, enzyme release, or phosphorylation of the mitogen-activated protein (MAP) kinase ERK and induces a weak chemotaxis in monocytes. instead, eotaxin-3 inhibits MCP-1-mediated responses, thus acting as a natural antagonist for CCR2. This study also demonstrates that eotaxin-3 promotes active movement of monocytes away from a gradient of eotaxin-3 in vitro. This repellent effect is amplified when an additional gradient of MCP-1 is applied, demonstrating that the 2 mechanisms are synergistic. Eotaxin-3 effects on monocytes; are largely abolished when cells are pretreated with MCP-1 or CCR2 antagonists Like MCP-1-mediated migration, repulsion is sensitive to Bordetella pertussis toxin, indicating the involvement of G(i) protein-coupled receptors. However, using transfected cells expressing CCR2 we could not detect F-actin formation or an active movement away induced by eotaxin-3, suggesting that either expression of a single receptor type is not sufficient to mediate cell repulsion or that the used transfected cell lines lack additional interaction molecules that are required for reverse migration. Eotaxin-3 was expressed by vascular endothelial cells and was essential for endothelial transmigration of eosinophils. Our data provide a mechanism by which 2 chemokine gradients that are oriented in opposite directions could cooperate in efficiently driving out monocytes from blood vessels into tissue.