Inhibition of acute peritoneal inflammation in rats by a cytokine-induced neutrophil chemoattractant receptor antagonist

Cytokine-induced neutrophil chemoattractant (CINC), a member of the IL-8 superfamily of chemokines, is one rat homologue of the three human GRO proteins, Neutralizing Abs against CINC have been shown previously to be efficacious in several models of inflammation, indicating that CINC is an important proinflammatory mediator in vivo. By introducing the N-terminal mutation Delta 1-5,ELR>AAR into CINC, we have developed a rat alpha-chemokine receptor antagonist (ra) analogous to a previously described mutant of human IL-8, Bacterially expressed CINCra had no chemotactic activity itself, but completely blocked the activity of physiologic concentrations of CINC when used as an antagonist in vitro. Inhibition by CINCra was specific, since it had approximately 10-fold less antagonist activity on the related, but distinct rat alpha-chemokine macrophage-inflammatory protein 2. When coinjected with zymosan into the peritoneal cavities of Lewis rats, 100 mu g of CINCra inhibited neutrophil influx by similar to 40%, which was comparable with inhibition caused by polyclonal anti-CINC Abs.