POMC gene-derived peptides activate melanocortin type 3 receptor or murinemacrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation

To investigate-the relevance of adrenocorticotrophic hormone (ACTH) therapy in human gouty arthritis, we have tested the effect of several ACTH-relate d peptides in a murine model of experimental gout, Systemic treatment of mi ce with ACTH(4-10) (MEH-FRWG) (10-200 mu g s.c.) inhibited neutrophil accum ulation without altering peripheral blood cell counts or circulating cortic osterone levels, A similar effect was seen with alpha- and beta-melanocyte stimulating hormones (1-30 mu g s.c.), In vivo release of the chemokine KC- (detected in the lavage fluids before maximal influx of neutrophils) was si gnificantly reduced (-50 to -60%) by ACTH(4-10). Macrophage activation in v itro, determined as phagocytosis and KC. release, was inhibited by ACTH and ACTH(4-10) with approximate IC50 values of 30 nM and 100 mu M, respectivel y. The melanocortin receptor type 3/4 antagonist SHU9119 prevented the inhi bitory actions of ACTH(4-10) both in vitro and in vivo. However, melanocort in type 3, but not type 4, receptor mRNA was detected in mouse peritoneal m acrophages by RT-PCR, Therefore, we propose that activation of this recepto r type by ACTH(4-10) and related amino acid sequences. attenuates RC releas e land possibly production of other cytokines) from macrophages with conseq uent, inhibition of the host inflammatory response, thus providing a notion al anti-inflammatory mechanism for ACTH that is unrelated to stimulation of glucocorticoid release.