Received for publication July 14, 2006.
Revised September 7, 2006.
Accepted for publication September 7, 2006.

[D-TRP⁸]--MSH exhibits anti-inflammatory efficacy in mice bearing a non-functional MC1R (recessive yellow e/e mouse)

Abstract

Two melanocortin receptors (MC1 and MC3R) have been suggested to be involved in modulating the host inflammatory response. Here we have addressed this aspect using a dual pharmacological and genetic approach, taking advantage of the selective MC3R agonist [D-TRB⁸]--MSH and the recessive yellow (e/e) mouse which has a non-functional MC1R. Cultured peritoneal macrophages taken from recessive yellow (e/e) mice were incubated for 30 min with [D-TRP⁸]--MSH, this led to accumulation of cAMP, indicating receptor functionality. This increase in cAMP was blocked in the presence of a neutralizing antibody against MC3R. Release of the pro-inflammatory chemokine KC by urate crystals was attenuated by [D-TRP⁸]--MSH and blocked in the presence of synthetic (SHU9119) and natural (AGRP) MC3R antagonists but not the MC4R antagonist HS024. Systemic treatment of mice with [D-TRP⁸]--MSH inhibited KC release and PMN accumulation elicited by urate crystals in the murine peritoneal cavity. SHU9119 and AGRP prevented the inhibitory actions of [D-TRP⁸]--MSH whilst HS024 was inactive. We also demonstrate here that [D-TRP⁸]--MSH displays a dual mechanism of action by inducing the anti-inflammatory protein HO-1. Treatment with the HO-1 inhibitor ZnPPIX exacerbates the inflammatory response elicited by urate crystals and abrogates the anti-inflammatory effects of [D-TRP⁸]--MSH. In conclusion, this data highlights that the selective MC3R agonist[D-TRP⁸]--MSH displays anti-inflammatory effects initially by inhibiting cytokine/chemokine generation and at later time-points inducing the anti-inflammatory protein HO-1.

Key words: Neuropeptides, ACTH, Leukocytes/Mast cells