title: Regulation of TNF-alpha secretion by a specific melanocortin-1 receptor peptide agonist.
abstract: The lack of specific pharmacological tools has impeded the evaluation of the role of each melanocortin receptor (MCR) subtype in the myriad physiological effects of melanocortins. 154N-5 is an octapeptide (MFRdWFKPV-NH(2)) that was first identified as an MC1R antagonist in Xenopus melanophores [J. Biol. Chem. 269 (1994) 29846]. In this manuscript, we show that 154N-5 is a specific agonist for human and murine MC1R. The peptide has negligible activity at MC3R and MC4R and is 25-fold less potent and a weak agonist at MC5R. 154N-5 was tested in both a cellular and an animal model of tumor necrosis factor-alpha (TNF-alpha) secretion. The inhibitory efficacy of 154N-5 on TNF-alpha secretion in both models was similar to the nonselective agonist NDP-alpha-melanocyte stimulating hormone (NDP-alphaMSH), thus, we conclude that inhibition of TNF-alpha secretion by melanocortin peptides is mediated by MC1R. 154N-5 is a valuable new tool for the evaluation of specific contribution of MC1R agonism to physiological and pathological processes.
authors.affiliation: Department of Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. diane.m.ignar@gsk.com
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ignar
authors.forename: John L
authors.initials: JL
authors.lastname: Andrews
authors.forename: Marilyn
authors.initials: M
authors.lastname: Jansen
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Eilert
authors.forename: Heather M
authors.initials: HM
authors.lastname: Pink
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Lin
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Sherrill
authors.forename: Jerzy R
authors.initials: JR
authors.lastname: Szewczyk
authors.forename: James G
authors.initials: JG
authors.lastname: Conway
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000032:analysis; D044101:Receptors, Melanocortin / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: C483732:154N-5 peptide; D008024:Ligands; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012333:RNA, Messenger; D044102:Receptor, Melanocortin, Type 1; D044101:Receptors, Melanocortin; D014409:Tumor Necrosis Factor-alpha