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Accelerated Communication

[D-Trp⁸]--Melanocyte-Stimulating Hormone Exhibits Anti-Inflammatory Efficacy in Mice Bearing a Nonfunctional MC1R (Recessive Yellow e/e Mouse)

The William Harvey Research Institute, Charterhouse Square, London, United Kingdom (S.J.G., C.W.L., F.N.E.G., G.L., M.P.); and Department of Pharmaceutical Chemistry and Toxicology, Universitá di Napoli, Naples, Italy (P.G.)

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]--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]--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]--MSH, and this effect was prevented by synthetic [Ac-Nle⁴-c[Asp⁵-2'-Nal⁷,Lys¹⁰]-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]--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]--MSH, whereas HS024 was inactive. We also demonstrate here that [D-Trp⁸]--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]--MSH. In conclusion, these data support the development of the selective MC3R agonist [D-Trp⁸]--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.

Address correspondence to: Stephen J. Getting, PhD, Senior Lecturer in Pharmacology, School of Biosciences, Department of Human and Health Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW United Kingdom. E-mail: s.getting{at}westminster.co.uk