title: Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia.
abstract: Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.
authors.affiliation: III Division of Internal Medicine, IRCCS Ospedale Maggiore, Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Delgado
authors.forename: A
authors.initials: A
authors.lastname: Carlin
authors.forename: L
authors.initials: L
authors.lastname: Airaghi
authors.forename: M T
authors.initials: MT
authors.lastname: Demitri
authors.forename: L
authors.initials: L
authors.lastname: Meda
authors.forename: D
authors.initials: D
authors.lastname: Galimberti
authors.forename: P
authors.initials: P
authors.lastname: Baron
authors.forename: J M
authors.initials: JM
authors.lastname: Lipton
authors.forename: A
authors.initials: A
authors.lastname: Catania
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D009500:Neutralization Tests; D009569:Nitric Oxide / Q000096:biosynthesis*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000521:alpha-MSH; C043156:MSH (11-13); D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones