Abstract
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.
Footnotes
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Research was funded by Research Advisory Board, St. Bartholomew's and the Royal London School of Medicine and Dentistry (grant RAB04/PJ/04) and by the Arthritis Research Campaign UK (grant 17299).
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ABBREVIATIONS: MSH, melanocyte-stimulating hormone; MØ, macrophage; HO-1, heme-oxygenase 1; MSU, monosodium urate; PBS, phosphate-buffered saline; ZnPPIX, zinc protoporphyrin IX; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; SHU9119, Ac-Nle4-c[Asp5-2′-Nal7,Lys10]α-MSH(4-10)-NH2; AGRP, agouti-related peptide; MTII, melanotan II; HS024, Ac-Cys-Nle-Arg-His-d-2-Nal-Arg-Trp-Cys-NH2.
- Received July 14, 2006.
- Accepted September 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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