Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists

In this study, we have examined the ability of chemokine receptor antagonis ts to prevent neutrophil extravasation in the mouse, Two murine CXC chemoki nes, macrophage-inflammatory protein (MIP)-2 and KC, stimulated the accumul ation of leukocytes into s.c. air pouches, although MIP-2 was considerably more potent. The leukocyte infiltrate was almost exclusively neutrophilic i n nature. A human CXC chemokine antagonist, growth-related oncogene (GRO)-a lpha(8-73), inhibited calcium mobilization induced by MIP-2, but not by pla telet-activating factor in leukocytes isolated from the bone marrow, indica ting that this antagonist inhibits MIP-2 activity toward murine leukocytes, Pretreatment of mice with GRO alpha(8-73) inhibited, in a dose-dependent m anner, the MIP-2-induced influx of neutrophils to levels that were not sign ificantly different from control values. Moreover, this antagonist was also effective in inhibiting the leukocyte recruitment induced by TNF-alpha, LP S, and IL-1 beta. Leukocyte infiltration into the peritoneal cavity in resp onse to MIP-2 was also inhibited by prior treatment of mice with GRO alpha( 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 c avity in response to proinflammatory agents and 2) that CXCR2 receptor anta gonists prevent acute inflammation in vivo.