α-Melanocyte stimulating hormone (α-MSH) and other melanocortin peptides are potent anti-inflammatory agents that exhibit efficacy in many animal models of acute and chronic inflammation. These peptides are produced both centrally and peripherally, and exert their biological actions via activation of membrane-bound receptors. To exploit the therapeutic potential of such anti-inflammatory peptides, it is essential that the receptor subtype mediating these effects is identified with certainty.
α-MSH has long been reported to be active in models of allergic and chronic inflammation, potently suppressing oedema formation and inhibiting leukocyte migration. Some α-MSH actions might be due to the C-terminal tripeptide KPV that corresponds to α-MSH 11–13 (Fig. 1b). For example, the KPV tri-peptide antagonizes the binding of interleukin 1β (IL-1β) to its receptor, suggesting that α-MSH might also function as an IL-1 receptor antagonist [3]. This action might explain the anti-pyretic effect
Two receptor candidates (MC 3 and MC 1) with different tissue distributions and levels of cellular expression have been proposed to be responsible for modulating the anti-inflammatory effects of melanocortin.
The MC 1 receptor has long been regarded as the receptor responsible for the anti-inflammatory effects of α-MSH and related peptides [1]. Using flow cytometry, Anderson et al. found expression of MC 1 receptor in monocytes, B cells, natural killer cells and a subset of cytoxic T cells, but not
Until recently, most studies have focused on the anti-inflammatory effects of melanocortin peptides in experimental models of acute and, to a lesser extent, chronic inflammation. Melanocortins have multiple biological actions; for example, they exert a protective effect in a rat model of myocardial infarct [17] and in models of endotoxin-induced colonic inflammation [18] and mesenteric ischaemia–reperfusion injury [19]. Other disease models have been shown to be susceptible to melanocortin
The role played by melanocortin peptides in modulating the host inflammatory response is beyond doubt. Along with many other anti-inflammatory substances these peptides play a protective role in maintaining the homeostatic balance within the body. The receptor type involved in modulating the inflammatory response has yet to be identified with certainty, although the availability of mice with non-functional MC 1 receptors or the generation of knockout MC 3 receptors [20] will help to address this
I would like to thank the Arthritis Research Campaign, UK (grant no. PO562) for their continued support.
