title: A role for MC3R in modulating lung inflammation.
abstract: In this study we set out to ascertain whether melanocortin peptides could be potential therapeutic agents in allergic and non-allergic models of lung inflammation by identifying the receptor(s) involved using a molecular, genetic and pharmacological approach. Western blot analyses revealed expression of the melanocortin receptor (MCR) type 1 and 3 on alveolar macrophages from wild-type mice. Alveolar macrophage incubation, with the selective MC3R agonist [D-TRP(8)]-gamma-MSH and pan-agonist alpha-MSH but not the selective MC1R agonist MS05, led to an increase in cAMP in wild-type macrophages. This increase occurred also in macrophages taken from recessive yellow (e/e; bearing a mutant and inactive MC1R) mice but not from MC3R-null mice. In an allergic model of inflammation, the pan-agonist alpha-MSH and selective MC3R agonist [D-TRP(8)]-gamma-MSH displayed significant attenuation of both eosinophil and lymphocyte accumulation but not IL-5 levels in wild-type and recessive yellow e/e mice. However in MC3R-null mice, alpha-MSH failed to cause a significant inhibition in these parameters, highlighting a preferential role for MC3R in mediating the anti-inflammatory effects of melanocortins in this model. Utilising a non-allergic model of LPS-induced lung neutrophilia, the pan-agonist alpha-MSH and selective MC3R agonist [D-TRP(8)]-gamma-MSH displayed significant attenuation of neutrophil accumulation and inhibition of TNF-alpha release. Thus, this study highlights that melanocortin peptides inhibit leukocyte accumulation in a model of allergic and non-allergic inflammation and this protective effect is associated with activation of the MC3R. The inhibition of leukocyte accumulation is via inhibition of TNF-alpha in the non-allergic model of inflammation but not IL-5 in the allergic model. These data have highlighted the potential for selective MC3R agonists as novel anti-inflammatory therapeutics in lung inflammation.
authors.affiliation: Department of Human and Health Sciences, School of Biosciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK. s.getting@westminster.ac.uk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Getting
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.forename: Simon
authors.initials: S
authors.lastname: Pitchford
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kaneva
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D004804:Eosinophils / Q000378:metabolism; D015848:Interleukin-5 / Q000737:chemistry; D008214:Lymphocytes / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D053486:Melanocortins / Q000494:pharmacology; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010455:Peptides / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry; D000521:alpha-MSH / Q000819:agonists / Q000494:pharmacology*; D019825:gamma-MSH / Q000819:agonists / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D015848:Interleukin-5; C408884:MS05 peptide; D053486:Melanocortins; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D014409:Tumor Necrosis Factor-alpha; D019825:gamma-MSH; C534065:gamma-melanocyte-stimulating factor, Trp(8)-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones