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 in®ltration following intradermal injection or peripheral blood eosinophilia following intravenous injection were compared in the Brown-Norway rat. 2 Eotaxin (0.1 ± 3 mg site 71 ) 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 mg site 71 whereas the latter did produce a small e ect at 3 mg site 71 . 4 Consistent with observations in vivo, human eotaxin displaced [ 125 I]-eotaxin from rat spleen membranes more potently (IC 50 =2 nM) than did MCP-4 (IC 50 =500 nM). RANTES did not compete with the radiolabelled chemokine at concentrations up to 1 mM. 5 Human eotaxin (5 mg) administered intravenously increased circulating eosinophils *3 fold whereas MCP-4 (5 mg, i.v.) increased circulating monocytes *3 fold without a ecting eosinophil numbers. 6 Dexamethasone pretreatment inhibited eotaxin-induced dermal eosinophil in¯ux only at a steroid dose (0.1 mg kg 71 , s.c.) which signi®cantly reduced circulating eosinophil numbers. The steroid also reduced eosinophilia in peripheral blood resulting from systemic eotaxin administration (5 mg, i.v.). 7 These data suggest di erences in rat CCR3 relative to other species as surmised from a distinctive rank order of chemokine potency. In addition to its chemotactic e ects 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 in¯ux is to diminish the circulating numbers of these cells available for tissue recruitment.

Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

“…CCL11 injection (29). Later on, it has been demonstrated that human CCL11 is able to cause a dose-dependent increase of circulating eosinophils in the BN rat, which is ϳ3-fold higher than the vehicle (33). The increased mobilization in F344 rats expressing DPPIV is similar, peaking 30 min after i.v.…”

“…The cutaneous recruitment of eosinophils in rats is supposed to be modulated by DPPIV, as it has been shown that DPPIV is present in rat epidermis (35). Furthermore, the capacity of human CCL11 to attract eosinophils to rat skin has been shown previously (33). A dose-dependent infiltration could be observed in DPPIV pos and DPPIV neg rats.…”

“…Moreover, it is conceivable, that the DPPIV activity in vivo is even higher, as soluble activity in serum, cell bound activity from T cells and from endothelial cells contribute to overall DPPIV activity. Interestingly, it has been shown that DPPIV activity is found in skin at a significantly higher amount than in serum and that N-terminally truncated CCL11 (desGP) has been purified from supernantants of cultured skin fibroblasts (33,34).…”

A Potent Human Anti-Eotaxin1 Antibody, CAT-213: Isolation by Phage Display and in Vitro and in Vivo Efficacy

“…Rodent, human, and murine eotaxin1 have been shown to be equieffective in terms of inducing eosinophil chemotaxis in vivo (Kudlacz et al, 1999). In this study, human eotaxin1 caused a marked increase in leukocyte recruitment after 6 h when administered to the air pouch of ovalbumin-sensitized mice pretreated with IL-5.…”

Selective suppression of leukocyte recruitment in allergic inflammation

“…Human CCR3 binds Eotaxin-1, Eotaxin-2, Eotaxin-3 and MCP-4 with high affinity, whereas RANTES and MCP-3 bind with lower affinity. Guinea pig Eotaxin-1 is highly potent as a stimulator of human eosinophils ) but, conversely, human Eotaxin-1 is inactive on guinea pig cells, although it is active on rat eosinophils (Sanz et al 1998, Kudlacz et al 1999. Despite the fact that human RANTES stimulates human eosinophils, RANTES from other species has, in general, low activity on homologous eosinophils (Campbell et al 1997).…”