title: Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes.
abstract: 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 Gi 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.
authors.affiliation: Institute for Research in Biomedicine, Via Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ogilvie
authors.forename: Samantha
authors.initials: S
authors.lastname: Paoletti
authors.forename: Ian
authors.initials: I
authors.lastname: Clark-Lewis
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
mesh_terms: D002118:Calcium / Q000378:metabolism; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D011485:Protein Binding; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D014162:Transfection
chemical_list: C120429:CCL26 protein, human; C515334:CCR2 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium