* University of Michigan Medical School, Department of Pathology, Ann Arbor;
Schering-Plough Research Institute, Department of Immunology, Kenilworth, New Jersey; and
National Center of Biotechnology, Dept. of Immunology and Oncology, Madrid, Spain
Correspondence: Nicholas W. Lukacs, University of Michigan Medical School, Dept. of Pathology, 1301 Catherine St., Ann Arbor, MI, 48109-0602. E-mail: nlukacs{at}umich.edu
In the present study, we investigated the regulation of chemokine-mediated responses and receptor expression on eosinophils from mice. MIP-1
(CCL3) and eotaxin (CCL11) induced a significant and only partially overlapping intracellular calcium flux in antigen-elicited and peripheral blood eosinophils, and MCP-1 (CCL2), MDC (CCL22), MIP-1ß (CCL4), and TCA-3 (CCL1) did not. To demonstrate functional use of the specific receptors, we examined chemotactic responses. Peripheral blood eosinophils migrated toward MIP-1 (CCL3) and eotaxin (CCL11) but not MCP-1 (CCL2), MDC (CCL22), MIP-1ß (CCL4), and TCA-3 (CCL1). Antigen-elicited eosinophils migrated toward MIP-1 (CCL3) and eotaxin (CCL11), but also migrated in response to MIP-1ß (CCL4) and TCA-3 (CCL1), suggesting the up-regulation of additional chemokine receptors on antigen-elicited eosinophils. The up-regulation of the additional chemokine-receptor responses appeared to be in part because of cytokine activation, because TNF- and/or IL-4 were able to up-regulate CCR1, -3, -5, and -8 mRNA expression in eosinophils as well as migration responses to the appropriate ligands. Using antibodies specific for CCR5 and CCR8, the chemotactic response to MIP-1ß and TCA-3, respectively, was reduced significantly. Finally, the expression of these new receptors appears to have an effect on activation and degranulation because MIP-1ß (CCL4) and TCA-3 (CCL1) induce significant levels of LTC4 from elicited eosinophils. These results suggest that eosinophils may up-regulate and use additional chemokine receptors during progression of inflammatory, allergic responses for migration and activation.
Key Words: allergy • chemokine receptors • chemotaxis • eosinophil recruitment
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