title: Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agents.
abstract: Alpha-melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide found mainly in the brain, pituitary, and circulation. It inhibits most forms of inflammation by a mechanism that is not known. As most types of inflammation require activation of NF-kappa B, we investigated the effect of alpha-MSH on the activation of this transcription factor by a wide variety of inflammatory stimuli. Electrophoretic mobility shift assay showed that alpha-MSH completely abolished TNF-mediated NF-kappa B activation in a dose- and time-dependent manner. It also suppressed NF-kappa B activation induced by LPS, okadaic acid, and ceramide. The effect was specific, as the activation of the transcription factor activating protein-1 by TNF was unaffected. Western blot analysis revealed that TNF-dependent degradation of the inhibitory subunit of NF-kappa B, I kappa B alpha, and nuclear translocation of the p65 subunit of NF-kappa B were also inhibited. This correlated with suppression of NF-kappa B-dependent reporter gene expression induced by TNF. The inhibitory effect of alpha-MSH appeared to be mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Similarly, addition of membrane-permeable dibutyryl cAMP, like alpha-MSH, suppressed TNF-induced NF-kappa B activation. Overall, our results suggest that alpha-MSH suppresses NF-kappa B activated by various inflammatory agents and that this mechanism probably contributes to its anti-inflammatory effects.
authors.affiliation: Department of Molecular Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Manna
authors.forename: B B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000276:immunology; D000242:Cyclic AMP / Q000502:physiology; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D005910:Glioma; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D002518:Ceramides; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D000521:alpha-MSH; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase