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a-Melanocyte-stimulating hormone (a-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of a-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 a-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon Y.a-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. a-MSH increased cAMP accumulation in RAW cells, characteristic of a-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary c-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecule of a-MSH, was expressed in RAW cells, and tumor necrosis factor a increased production and release of cv-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor a can induce macrophages to increase production of c-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 a-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.The neuropeptide a-melanocyte-stimulating hormone (a-MSH), a derivative of proopiomelanocortin (POMC), found in the pituitary, brain, skin, circulation, and other sites, has potent antiinflammatory activity. a-MSH reduces fever (1, 2) and the following: (i) acute inflammation caused by irritants or by local mediators, such as cytokines (3, 4); (ii) delayed hypersensitivity responses, a model of allergic reactions (5, 6); (iii) chronic inflammation (mycobacterium-induced arthritis) (7,8); and (iv) systemic inflammation (e.g., endotoxemia and sepsis) (8, 9). Although a-MSH antagonizes the actions of proinflammatory cytokines (1, 2, 4, 9, 10), the precise mechanism of its antiinflammatory action is unknown. a-MSH was recently identified in synovial fluid of patients with rheumatoid arthritis (11). Thus, a-MSH is produced at sites of inflammation, although the cell type(s) responsible is unknown.a-MSH functions via melanocortin (MC) receptors (12-18). There are five subtypes of MC receptors (MC-1 through MC-5). These receptors contain seven membrane-spanning domains typical of G-protein-coupled receptors, and are coupled to adenylate cyclase to generate cAMP. MC receptors are differentially expressed in a restricted distribution, with MC-1 identified in melanoma cells and melanocytes but not in brain, adrenal, or other tissues by mRNA blotting (12, 13).That a-MSH has a wide spectrum of antiinflammatory activity suggests that the peptide inhibits a critical agent or event that is common to multiple forms of inflammatio...

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Melanocortin peptides, the collective term for α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, γ-MSH) and adrenocorticotropic hormone (ACTH), are elements of an ancient modulatory system. Natural melanocortins derive from the common precursor pro-opiomelanocortin (POMC). Five receptor subtypes for melanocortins (MC1-MC5) are widely distributed in brain regions and in peripheral cells. Melanocortin receptor activation by natural or synthetic ligands exerts marked anti-inflammatory and immunomodulatory effects. The anticytokine action and the inhibitory influences on inflammatory cell migration make melanocortins potential new drugs for treatment of inflammatory disorders. Effectiveness in treatment of acute, chronic, and systemic inflammatory disorders is well documented in preclinical studies. Further, melanocortins are promising compounds in neuroprotection. This review examines the main signaling circuits in anti-inflammatory and immunomodulatory actions of melanocortins, and the potential therapeutic use of these molecules.

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alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.