title: Characterization of chemokine CCR3 agonist-mediated eosinophil recruitment in the Brown-Norway rat.
abstract: 1. The ability of various C-C chemokines to elicit tissue eosinophil infiltration following intradermal injection or peripheral blood eosinophilia following intravenous injection were compared in the Brown-Norway rat. 2. Eotaxin (0.1 - 3 microg site-1) of human and murine origin produced equivalent, dose-dependent increases in eosinophil peroxidase activity in rat dermis 4 h post-injection. 3. Human eotaxin-2 was equipotent with human eotaxin in terms of dermal eosinophil recruitment. Other human CCR3 agonists, such as MCP-3, RANTES and MCP-4 failed to increase dermal eosinophil peroxidase activity at doses up to 1 microg site-1 whereas the latter did produce a small effect at 3 microg site-1. 4. Consistent with observations in vivo, human eotaxin displaced [125I]-eotaxin from rat spleen membranes more potently (IC50=2 nM) than did MCP-4 (IC50=500 nM). RANTES did not compete with the radiolabelled chemokine at concentrations up to 1 microM. 5. Human eotaxin (5 microg) administered intravenously increased circulating eosinophils approximately 3 fold whereas MCP-4 (5 microg i.v.) increased circulating monocytes approximately 3 fold without affecting eosinophil numbers. 6. Dexamethasone pretreatment inhibited eotaxin-induced dermal eosinophil influx only at a steroid dose (0.1 mg kg-1, s.c.) which significantly reduced circulating eosinophil numbers. The steroid also reduced eosinophilia in peripheral blood resulting from systemic eotaxin administration (5 microg, i.v.). 7. These data suggest differences in rat CCR3 relative to other species as surmised from a distinctive rank order of chemokine potency. In addition to its chemotactic effects eotaxin, but not MCP-4, promotes eosinophil recruitment into the circulation. One of the mechanisms by which glucocorticoids, such as dexamethasone, acutely inhibits eotaxin-induced dermal eosinophil influx is to diminish the circulating numbers of these cells available for tissue recruitment.
authors.affiliation: Pfizer Central Research, Eastern Point Road, Groton, Connecticut, CT 06340, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Kudlacz
authors.forename: C A
authors.initials: CA
authors.lastname: Whitney
authors.forename: C J
authors.initials: CJ
authors.lastname: Andresen
authors.forename: J P
authors.initials: JP
authors.lastname: Umland
authors.forename: J B
authors.initials: JB
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects; D054413:Chemokine CCL11; D018925:Chemokines / Q000494:pharmacology; D019742:Chemokines, CC; D016207:Cytokines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051381:Rats; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000819:agonists*; D015728:Receptors, HIV / Q000819:agonists*
chemical_list: D000893:Anti-Inflammatory Agents; C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515458:Ccl11 protein, rat; C515352:Ccr3 protein, rat; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D015728:Receptors, HIV; D003907:Dexamethasone