Em. Kudlacz et al., Characterization of chemokine CCR3 agonist-mediated eosinophil recruitmentin the Brown-Norway rat, BR J PHARM, 128(3), 1999, pp. 788-794
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.