Natural and synthetic agonists of the melanocortin receptor type 3 possess anti-inflammatory properties.
The effects of the natural and synthetic ligands for the melanocortin receptor type 3 (MC3-R) have been evaluated in a murine model of experimental gout. Systemic treatment of mice with gamma2-melanocyte-stimulating hormone (gamma2-MSH) and the synthetic agonist MTII inhibited accumulation of KC, interleukin-1 beta (IL-1beta), and PMN elicited by urate crystals in the peritoneal cavity. In vitro, macrophage (Mø) activation, determined as release of KC and IL-1beta, was inhibited by gamma2-MSH and MTII. The mixed MC3/4-R antagonist SHU9119 prevented the inhibitory actions of gamma2-MSH and MTII in vitro and in vivo, whereas the selective MC4-R antagonist HS024 was without effect. Western blotting also showed the presence of MC3-R protein on murine peritoneal Mø. Furthermore, agonism at the MC3-R evoked accumulation of cAMP within the Mø, which was inhibited by SHU9119. Thus, naturally occurring melanocortins, as well as the synthetic long-acting compound MTII, activate MC3-R on peritoneal Mø to inhibit the experimental inflammatory response.
Getting
S J
SJ
The William Harvey Research Institute, London, England. S.J.Getting@mds.qmw.ac.uk
Allcock
G H
GH
Flower
R
R
Perretti
M
M
D000818:Animals; D006073:Gout / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000276:immunology; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use*
D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones