%0 Journal Article %A Stephen J. Getting %A Connie W. Lam %A Giovanna Leoni %A Felicity N. E. Gavins %A Paolo Grieco %A Mauro Perretti %T [d-Trp8]-γ-Melanocyte-Stimulating Hormone Exhibits Anti-Inflammatory Efficacy in Mice Bearing a Nonfunctional MC1R (Recessive Yellow e/e Mouse) %D 2006 %R 10.1124/mol.106.028878 %J Molecular Pharmacology %P 1850-1855 %V 70 %N 6 %X Two melanocortin receptors (MC1 and MC3R) have been identified as main transducers of the anti-inflammatory effects of natural and synthetic melanocortins. In this study, we have taken advantage of the recent description of the selective MC3R agonist [d-Trp8]-γ-melanocyte-stimulating hormone (MSH) and of the recessive yellow (e/e) mouse, bearing a nonfunctional MC1R, thereby incrementing our knowledge on this topic. Culturing peritoneal macrophages of recessive yellow (e/e) mice with [d-Trp8]-γ-MSH led to accumulation of cAMP, indicating MC3R receptor functionality: this effect was blocked by a neutralizing antibody against MC3R. Likewise, release of the chemokine KC by urate crystals was attenuated by [d-Trp8]-γ-MSH, and this effect was prevented by synthetic [Ac-Nle4-c[Asp5-2′-Nal7,Lys10]α-MSH(4-10)-NH2 (SHU9119)] and natural [agouti-related protein (AGRP)] MC3R antagonists but not by the MC4R antagonist Ac-Cys-Nle-Arg-His-d-2-Nal-Arg-Trp-Cys-NH2 (HS024). Systemic treatment of mice with [d-Trp8]-γ-MSH inhibited KC release and polymorphonuclear cell accumulation elicited by urate crystals in the murine peritoneal cavity. SHU9119 and AGRP prevented the inhibitory actions of [d-Trp8]-γ-MSH, whereas HS024 was inactive. We also demonstrate here that [d-Trp8]-γ-MSH displays a dual mechanism of action by inducing the anti-inflammatory protein heme-oxygenase 1 (HO-1). Treatment with the HO-1 inhibitor zinc protoporphyrin IX exacerbated the inflammatory response elicited by urate crystals and abrogated the anti-inflammatory effects of [d-Trp8]-γ-MSH. In conclusion, these data support the development of the selective MC3R agonist [d-Trp8]-γ-MSH for the treatment of inflammatory pathologies, based on a dual mechanism of cytokine/chemokine inhibition and induction of the anti-inflammatory protein HO-1. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/70/6/1850.full.pdf