MELANOCORTIN PEPTIDES INHIBIT PRODUCTION OF PROINFLAMMATORY CYTOKINESAND NITRIC-OXIDE BY ACTIVATED MICROGLIA

Inflammatory processes contribute to neurodegenerative disease, stroke , encephalitis, and other central nervous system (CNS) disorders, Acti vated microglia are a source of cytokines and other inflammatory agent s within the CNS and it is therefore important to control glial functi on in order to preserve neural cells. Melanocortin peptides are pro-op iomelanocortin-derived amino acid sequences that include alpha-melanoc yte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (A CTH), 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), interleu kin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial ce ll line (N9) stimulated with lipopolysaccharide (LPS) pills interferon gamma (IFN-gamma), Melanocortin peptides inhibited production of thes e cytokines and NO in a concentration-related fashion, probably by inc reasing intracellular cAMP. When stimulated with LPS + IFN-gamma, micr oglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, a nd NO was greater in activated microglia after immunoneutralization of endog enous alpha-MSH. The results suggest that alpha-MSH is an autoc rine factor in microglia, Because melanocortin peptides inhibit produc tion of pro-inflammatory mediators by activated microglia they might b e useful in treatment of inflammatory/degenerative brain disorders.