Characterization of chemokine CCR3 agonist-mediated eosinophil recruitmentin the Brown-Norway rat

1 The ability of various C-C chemokines to elicit tissue eosinophil infiltr ation following intradermal injection or peripheral blood eosinophilia foll owing intravenous injection were compared in the Brown-Norway rat. 2 Eotaxin (0.1-3 mu g site(-1)) of human and murine origin produced equival ent, dose-dependent increases in eosinophil peroxidase activity in rat derm is 4 h post-injection. 3 Human eotaxin-2 was equipotent with human eotaxin in terms of dermal eosi nophil recruitment. Other human CCR3 agonists, such as MCP-3, RANTES and MC P;4 failed to increase dermal eosinophil peroxidase activity at doses up to 1 mu g site(-1) whereas the latter did produce a small effect at 3 mu g si te(-1). 4 Consistent with observations in vivo, human eotaxin displaced [I-125]-eot axin from rat spleen membranes more potently (IC50=2 nM) than did MCP-4 (IC 50=500 nM). RANTES did not compete with the radiolabelled chemokine at conc entrations up to 1 mu M. 5 Human eotaxin (5 mu g) administered intravenously increased circulating e osinophils similar to 3 fold whereas MCP-4 (5 mu g, i.v.) increased circula ting monocytes similar to 3 fold without affecting eosinophil numbers. 6 Dexamethasone pretreatment inhibited eotaxin-induced dermal eosinophil in flux only at a steroid dose (0.1 mg kg(-1), s.c.) which significantly reduc ed circulating eosinophil numbers. The steroid also reduced eosinophilia in peripheral blood resulting from systemic eotaxin administration (5 mu g, i .v.). 7 These data suggest differences in rat CCR3 relative to other species as s urmised from a distinctive rank order of chemokine potency. In addition to its chemotactic effects eotaxin, but not MCP-4, promotes eosinophil recruit ment into the circulation. One of the mechanisms by which glucocorticoids, such as dexamethasone, acutely inhibits eotaxin-induced dermal eosinophil i nflux is to diminish the circulating numbers of these cells available for t issue recruitment.