Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5.
Eotaxin is a potent inducer of eosinophil chemotaxis and was considered as a selective ligand of the CC chemokine receptor 3 (CCR3), which is expressed on eosinophils, basophils, and Th2 lymphocytes. This study shows that eotaxin also interacts with CCR2 and CCR5 and can, thus, affect the responses of monocytes, which express both receptors. In human monocytes pretreatment with eotaxin decreased responsiveness to MCP-1, a selective ligand for CCR2, as well as to RANTES and MIP-1 beta, which bind to CCR5. Similar effects were obtained with transfected cells expressing CCR2 or CCR5, but here a difference became apparent: Eotaxin triggered CCR5 at a concentration of 100 nM but not CCR2 even at 1 microM, suggesting an antagonistic effect on this receptor. In agreement with this observation, eotaxin induced internalization of CCR5 but not of CCR2 in human monocytes and transfected cells. Binding studies showed that eotaxin displaces (125) I-MCP-1 from monocytes in a concentration-dependent manner, and functional experiments showed that eotaxin inhibits MCP-1-induced chemotaxis and enzyme release. The results demonstrate that eotaxin is a CCR5 agonist and a CCR2 antagonist. The present findings suggest a role of eotaxin in the fine-tuning of cellular responses occurring at sites of allergic inflammation, in which both MCP-1 and eotaxin are produced. (Blood. 2001;97:1920-1924)
Ogilvie
P
P
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Bardi
G
G
Clark-Lewis
I
I
Baggiolini
M
M
Uguccioni
M
M
D020013:Calcium Signaling / Q000187:drug effects; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000494:pharmacology; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D004802:Eosinophilia / Q000503:physiopathology; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000819:agonists*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D014162:Transfection
C515456:CCL11 protein, human; C515334:CCR2 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine