Anna Catania

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of alpha-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We measured NO and alpha-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon gamma. alpha-MSH inhibited production of NO, as estimated from nitrite production and nitration of endogenous macrophage proteins. This occurred through inhibition of production of NO synthase II protein; steady-state NO synthase II mRNA abundance was also reduced. alpha-MSH increased cAMP accumulation in RAW cells, characteristic of alpha-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary alpha-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecular of alpha-MSH, was expressed in RAW cells, and tumor necrosis factor alpha increased production and release of alpha-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor alpha can induce macrophages to increase production of alpha-MSH, which then becomes available to act upon melanocortin receptors on the same cells. Such stimulation of melanocortin receptors could modulate inflammation by inhibiting the production of NO. The results suggest that alpha-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.

α-MELANOCYTE-stimulating hormone (αMSH), a basic tridecapeptide, is derived from the precursor molecule POMC(l). The amino acid sequence of αMSH is identical to the 1–13 (N-terminal) amino acid sequence of ACTH although αMSH has little direct influence on glucocorticoid release from the adrenal gland. αMSH is found mainly in the pituitary, but it also occurs in lower concentrations in the central nervous system (CNS), the skin, and other sites (1). This peptide was named for its effect on pigmentation in amphibian skin, although its distribution in tissues of higher organisms suggests that it is important to other functions. Phylogenetically, αMSH is an “ancient” molecule, little changed over the last few hundred million years, and there is remarkable conservation of its amino acid sequence across species. Evidence that this endogenous neuropeptide is important to limitation of fever and inflammation in mammals, including man, suggests that αMSH has retained a role as a modulator of host responses (2–7).