Redundancy of a functional melanocortin 1 receptor in the anti-inflammatory actions of melanocortin peptides: studies in the recessive yellow (e/e) mouse suggest an important role for melanocortin 3 receptor.
The issue of which melanocortin receptor (MC-R) is responsible for the anti-inflammatory effects of melanocortin peptides is still a matter of debate. Here we have addressed this aspect using a dual pharmacological and genetic approach, taking advantage of the recent characterization of more selective agonists/antagonists at MC1 and MC3-R as well as of the existence of a naturally defective MC1-R mouse strain, the recessive yellow (e/e) mouse. RT-PCR and ultrastructural analyses showed the presence of MC3-R mRNA and protein in peritoneal macrophages (M phi) collected from recessive yellow (e/e) mice and wild-type mice. This receptor was functional as Mphi incubation (30 min) with melanocortin peptides led to accumulation of cAMP, an effect abrogated by the MC3/4-R antagonist SHU9119, but not by the selective MC4-R antagonist HS024. In vitro M phi activation, determined as release of the CXC chemokine KC and IL-1 beta, was inhibited by the more selective MC3-R agonist gamma(2)-melanocyte stimulating hormone but not by the selective MC1-R agonist MS05. Systemic treatment of mice with a panel of melanocortin peptides inhibited IL-1 beta release and PMN accumulation elicited by urate crystals in the murine peritoneal cavity. MS05 failed to inhibit any of the inflammatory parameters either in wild-type or recessive yellow (e/e) mice. SHU9119 prevented the inhibitory actions of gamma(2)-melanocyte stimulating hormone both in vitro and in vivo while HS024 was inactive in vivo. In conclusion, agonism at MC3-R expressed on peritoneal M phi leads to inhibition of experimental nonimmune peritonitis in both wild-type and recessive yellow (e/e) mice.
Getting
Stephen J
SJ
Department of Biochemical Pharmacology, The William Harvey Research Institute, Bart's and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom. S.J.Getting@qmul.ac.uk
Christian
Helen C
HC
Lam
Connie W
CW
Gavins
Felicity N E
FN
Flower
Roderick J
RJ
Schiöth
Helgi B
HB
Perretti
Mauro
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D003460:Crystallization; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005808:Genes, Recessive; D007274:Injections, Intraperitoneal; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D010858:Pigmentation / Q000235:genetics; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D044101:Receptors, Melanocortin; D014527:Uric Acid / Q000633:toxicity; D019825:gamma-MSH / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C470053:Mc3r protein, mouse; D044104:Receptor, Melanocortin, Type 3; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D019825:gamma-MSH; D014527:Uric Acid; D009074:Melanocyte-Stimulating Hormones