Evidence of Autocrine Modulation of Macrophage Nitric Oxide Synthase by α-Melanocyte-Stimulating Hormone

α-Melanocyte-stimulating hormone (α-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of α-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 17; pp. 8016 - 8020
Main Authors:	Star, Robert A., Rajora, Nilum, Huang, Jijing, Stock, Renee C., Catania, Anna, Lipton, J. M.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences of the United States of America 15-08-1995 National Acad Sciences National Academy of Sciences
Subjects:	alpha-MSH - pharmacology Amino Acid Oxidoreductases - biosynthesis Amino Acid Oxidoreductases - metabolism Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Arginine - analogs & derivatives Arginine - pharmacology Base Sequence Cell Line Complementary DNA Cytokines DNA Primers Endothelial cells Gene Expression - drug effects Hormones Humans Inflammation Interferon-gamma - pharmacology Lipopolysaccharides - pharmacology Macrophages Macrophages - drug effects Macrophages - metabolism Medical research Messenger RNA Mice Models, Biological Molecular Sequence Data Nitration Nitric Oxide - antagonists & inhibitors Nitric Oxide - biosynthesis Nitric Oxide Synthase Nitrites omega-N-Methylarginine Polymerase Chain Reaction Pro-Opiomelanocortin - biosynthesis Receptors Receptors, Corticotropin - biosynthesis Receptors, Melanocortin Recombinant Proteins RNA, Messenger - analysis RNA, Messenger - biosynthesis Salmonella typhi
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Summary:	α-Melanocyte-stimulating hormone (α-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of α-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 α-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon γ. α-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. α-MSH increased cAMP accumulation in RAW cells, characteristic of α-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary α-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecule of α-MSH, was expressed in RAW cells, and tumor necrosis factor α increased production and release of α-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor α can induce macrophages to increase production of α-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 α-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.92.17.8016