Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone.

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.

[1]  J. M. Lipton,et al.  Antiinflammatory Effects of the Neuropeptide α‐MSH in Acute, Chronic, and Systemic Inflammation a , 1994 .

[2]  Barry Halliwell,et al.  Evidence for nitric oxide‐mediated oxidative damage in chronic inflammation Nitrotyrosine in serum and synovial fluid from rheumatoid patients , 1994, FEBS letters.

[3]  R. Miller,et al.  Regulation of hormone-sensitive calcium influx by the adenylyl cyclase system in renal epithelial cells. , 1994, The Journal of clinical investigation.

[4]  C. Evans,et al.  N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. , 1994, Arthritis and rheumatism.

[5]  J. M. Lipton,et al.  The anticytokine neuropeptide alpha-melanocyte-stimulating hormone in synovial fluid of patients with rheumatic diseases: comparisons with other anticytokine molecules. , 1994, Neuroimmunomodulation.

[6]  Y. Konda,et al.  Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor. , 1994, The Journal of biological chemistry.

[7]  F. Trautinger,et al.  Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes. , 1994, The Journal of clinical investigation.

[8]  M. Parmentier,et al.  Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. , 1994, The Biochemical journal.

[9]  J. M. Lipton,et al.  The Neuropeptide Alpha-Melanocyte-Stimulating Hormone: A Key Component Neuroimmunomodulation , 1994 .

[10]  P G Anderson,et al.  Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. , 1994, Biological chemistry Hoppe-Seyler.

[11]  J. M. Lipton,et al.  Central neurogenic antiinflammatory action of alpha-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation. , 1994, Neuroendocrinology.

[12]  J. Trent,et al.  Mapping of the gene encoding the melanocortin-1 (alpha-melanocyte stimulating hormone) receptor (MC1R) to human chromosome 16q24.3 by Fluorescence in situ hybridization. , 1994, Genomics.

[13]  J. M. Lipton,et al.  Inhibition of IL-1β-induced peripheral inflammation by peripheral and central administration of analogs of the neuropeptide α-MSH , 1993, Brain Research Bulletin.

[14]  S. Moncada,et al.  The L-arginine-nitric oxide pathway. , 1993, The New England journal of medicine.

[15]  M. Mortrud,et al.  Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[16]  F. Liew,et al.  Nitric oxide production by murine macrophages is inhibited by prolonged elevation of cyclic AMP. , 1993, Biochemical and biophysical research communications.

[17]  A. Nussler,et al.  Inflammation, immunoregulation, and inducible nitric oxide synthase , 1993, Journal of leukocyte biology.

[18]  S. Watson,et al.  Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. , 1993, The Journal of biological chemistry.

[19]  R. Strieter,et al.  Interferon-gamma regulation of human renal cortical epithelial cell-derived monocyte chemotactic peptide-1. , 1993, Kidney international.

[20]  J. M. Lipton,et al.  α‐Melanocyte‐Stimulating Hormone Peptides in Host Responses From Basic Evidence to Human Research a , 1993 .

[21]  S. Watson,et al.  Molecular cloning of a novel melanocortin receptor. , 1993, The Journal of biological chemistry.

[22]  R. Star,et al.  Differential expression of mRNA for guanylyl cyclase-linked endothelium-derived relaxing factor receptor subunits in rat kidney. , 1993, The Journal of clinical investigation.

[23]  L. Raij,et al.  Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. , 1992, The Journal of clinical investigation.

[24]  J. Wikberg,et al.  Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA , 1992, FEBS letters.

[25]  M. Sporn,et al.  Autocrine Secretion—10 Years Later , 1992, Annals of Internal Medicine.

[26]  M. Mortrud,et al.  The cloning of a family of genes that encode the melanocortin receptors. , 1992, Science.

[27]  J. M. Lipton,et al.  α-MSH peptides inhibit acute inflammation induced in mice by rIL-1β, rIL-6, rTNF-α and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8 , 1992 .

[28]  S. Moncada.  The 1991 Ulf von Euler Lecture. The L-arginine: nitric oxide pathway. , 1992, Acta physiologica Scandinavica.

[29]  J. Cunningham,et al.  Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. , 1992, The Journal of biological chemistry.

[30]  S. Moncada,et al.  Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? , 1991, The Lancet.

[31]  S. Snyder,et al.  Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[32]  N. Boughton-Smith,et al.  Role of nitric oxide in maintaining vascular integrity in endotoxin‐induced acute intestinal damage in the rat , 1990, British journal of pharmacology.

[33]  J. M. Lipton,et al.  Alpha-MSH peptides inhibit acute inflammation and contact sensitivity , 1990, Peptides.

[34]  J. Nordlund,et al.  Alpha-melanocyte stimulating hormone modulates contact hypersensitivity responsiveness in C57/BL6 mice. , 1989, The Journal of investigative dermatology.

[35]  J. B. Tatro,et al.  Specific receptors for alpha-melanocyte-stimulating hormone are widely distributed in tissues of rodents. , 1987, Endocrinology.

[36]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[37]  M. Uhler,et al.  Complete amino acid sequence of mouse pro-opiomelanocortin derived from the nucleotide sequence of pro-opiomelanocortin cDNA. , 1983, The Journal of biological chemistry.

[38]  S. Tannenbaum,et al.  Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. , 1982, Analytical biochemistry.

[39]  P. Ralph,et al.  Functional macrophage cell lines transformed by abelson leukemia virus , 1978, Cell.

[40]  P. Ralph,et al.  Antibody-dependent killing of erythrocyte and tumor targets by macrophage-related cell lines: enhancement by PPD and LPS. , 1977, Journal of immunology.

[41]  H. Bourne,et al.  Modulation of Inflammation and Immunity by Cyclic AMP , 1974 .

[42]  C. Londos,et al.  A highly sensitive adenylate cyclase assay. , 1974, Analytical biochemistry.

[43]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[44]  J. M. Lipton,et al.  The neuropeptide alpha-melanocyte-stimulating hormone inhibits experimental arthritis in rats. , 1994, Neuroimmunomodulation.

[45]  A. Catania,et al.  alpha-Melanocyte stimulating hormone in the modulation of host reactions. , 1993, Endocrine reviews.

[46]  Coffey Rg,et al.  Neurotransmitters, hormones, and cyclic nucleotides in lymphocyte regulation. , 1985 .