title: Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists.
abstract: In this study, we have examined the ability of chemokine receptor antagonists to prevent neutrophil extravasation in the mouse. Two murine CXC chemokines, macrophage-inflammatory protein (MIP)-2 and KC, stimulated the accumulation of leukocytes into s.c. air pouches, although MIP-2 was considerably more potent. The leukocyte infiltrate was almost exclusively neutrophilic in nature. A human CXC chemokine antagonist, growth-related oncogene (GRO)-alpha(8-73), inhibited calcium mobilization induced by MIP-2, but not by platelet-activating factor in leukocytes isolated from the bone marrow, indicating that this antagonist inhibits MIP-2 activity toward murine leukocytes. Pretreatment of mice with GROalpha(8-73) inhibited, in a dose-dependent manner, the MIP-2-induced influx of neutrophils to levels that were not significantly different from control values. Moreover, this antagonist was also effective in inhibiting the leukocyte recruitment induced by TNF-alpha, LPS, and IL-1beta. Leukocyte infiltration into the peritoneal cavity in response to MIP-2 was also inhibited by prior treatment of mice with GROalpha(8-73) or the analogue of platelet factor 4, PF4(9-70). The results of this study indicate 1) that the murine receptor for MIP-2 and KC, muCXCR2, plays a major role in neutrophil recruitment to s.c. tissue and the peritoneal cavity in response to proinflammatory agents and 2) that CXCR2 receptor antagonists prevent acute inflammation in vivo.
authors.affiliation: Department of Microbiology and Immunology, University of Adelaide, Australia. smccoll@microb.adelaide.edu.au
authors.forename: S R
authors.initials: SR
authors.lastname: McColl
authors.forename: I
authors.initials: I
authors.lastname: Clark-Lewis
mesh_terms: D000818:Animals; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D006133:Growth Substances / Q000494:pharmacology; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology; D010538:Peritonitis / Q000517:prevention & control; D010978:Platelet Factor 4 / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D007106:Immune Sera; D036341:Intercellular Signaling Peptides and Proteins; D015846:Monokines; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D010978:Platelet Factor 4