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(Journal of Leukocyte Biology. 2001;69:98-104.)
© 2001 by Society for Leukocyte Biology

Natural and synthetic agonists of the melanocortin receptor type 3 possess anti-inflammatory properties

Stephen J. Getting, Graham H. Allcock, Roderick Flower and Mauro Perretti

The William Harvey Research Institute, Charterhouse Square, London, England

Correspondence: Stephen J. Getting, Ph.D., Department of Biochemical Pharmacology, The William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, England. E-mail: S.J.Getting{at}mds.qmw.ac.uk

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 {gamma}2-melanocyte-stimulating hormone ({gamma}2-MSH) and the synthetic agonist MTII inhibited accumulation of KC, interleukin-1 beta (IL-1ß), and PMN elicited by urate crystals in the peritoneal cavity. In vitro, macrophage (Mø) activation, determined as release of KC and IL-1ß, was inhibited by {gamma}2-MSH and MTII. The mixed MC3/4-R antagonist SHU9119 prevented the inhibitory actions of {gamma}2-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.

Key Words: {gamma}2-MSH • MTII • KC • IL-1ß • inflammation




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