Melanocortin 3 receptors control crystal-induced inflammation.
In this study we have characterized the anti-inflammatory profile of a selective melanocortin type 3 receptor (MC3-R) ligand [D-Trp8]-gamma-MSH, validating in vitro results with analyses in mice deficient for this receptor subtype. In wild-type (WT) macrophages, [D-Trp8]-gamma-MSH activated MC3-R (as tested by accumulation of cyclic AMP) and inhibited (approximately 50%) the release of interleukin (IL)-1 and the chemokine KC (CXCL1), but was ineffective in cells taken from MC3-R null mice. In vivo, administration of 3-30 microg [D-Trp8]-gamma-MSH significantly inhibited leukocyte influx and cytokine production in a model of crystal-induced peritonitis, and these effects were absent in MC3-R null mice or blocked by coadministration of an MC3-R antagonist. Finally, in a model of gouty arthritis, direct injection of urate crystals into the rat joint provoked a marked inflammatory reaction that was significantly inhibited (approximately 70%) by systemic or local administration of [D-Trp8]-gamma-MSH. In conclusion, using an integrated transgenic and pharmacological approach, we provide strong proof of concept for the development of selective MC3-R agonists as novel anti-inflammatory therapeutics.
Getting
Stephen J
SJ
The William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, UK.
Lam
Connie W
CW
Chen
Airu S
AS
Grieco
Paolo
P
Perretti
Mauro
M
D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology / Q000517:prevention & control; D015210:Arthritis, Gouty / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000517:prevention & control*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044101:Receptors, Melanocortin / Q000235:genetics / Q000502:physiology*; D014527:Uric Acid / Q000633:toxicity
C470053:Mc3r protein, mouse; D044104:Receptor, Melanocortin, Type 3; D044101:Receptors, Melanocortin; C514973:melanocortin 3 receptor, rat; D014527:Uric Acid