title: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells.
abstract: Respiratory epithelial cells are known to contribute to immune responses through the release of mediators. The aim of this study was to characterize the immunomodulatory effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco carcinogen, on respiratory epithelial cells and to compare two metabolic pathways, alpha-methylhydroxylation and alpha-methylenehydroxylation, involved in these effects using selective precursors, 4-(acetoxy-methylnitrosamino)-1-(3-pyridil)-1-butanone (NNKOAc) and N-nitroso (acetoxymethyl) methylamine (NDMAOAc), respectively. Human bronchial and alveolar epithelial cell lines, BEAS-2B and A549, respectively, were treated with NNK, NNKOAc and NDMAOAc for 24 h with and without tumour necrosis factor (TNF) and mediators released in cell-free supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NNK significantly inhibited interleukin (IL)-8, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production in both cell types. Similar results were observed with primary bronchial and alveolar epithelial cells. Although NNK increased prostaglandin E(2) (PGE(2)) production by A549 cells, its immunomodulatory effects were not mediated by PGE(2) according to the results with cyclo-oxygenase inhibitors. NNKOAc mimicked NNK effects, whereas NDMAOAc significantly inhibited IL-8 production in BEAS-2B cells and MCP-1 in both cell types. These results demonstrate that NNK and its reactive metabolites have immunosuppressive effects on respiratory epithelial cells, which could contribute to the increased respiratory infections observed in smokers and the development and/or the progression of lung cancer.
authors.affiliation: Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Sainte-Foy, Québec, Canada.
authors.forename: L I
authors.initials: LI
authors.lastname: Proulx
authors.forename: M
authors.initials: M
authors.lastname: Gaudreault
authors.forename: V
authors.initials: V
authors.lastname: Turmel
authors.forename: L A
authors.initials: LA
authors.lastname: Augusto
authors.forename: A
authors.initials: A
authors.lastname: Castonguay
authors.forename: E Y
authors.initials: EY
authors.lastname: Bissonnette
mesh_terms: D001980:Bronchi / Q000276:immunology*; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D006900:Hydroxylation; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D009602:Nitrosamines / Q000276:immunology* / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000276:immunology*; D011725:Pyridines / Q000276:immunology / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; D002273:Carcinogens; D018932:Chemokine CCL2; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D009602:Nitrosamines; D011725:Pyridines; C081510:4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone; C014659:methyl(acetoxymethyl)nitrosamine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D015232:Dinoprostone; D004128:Dimethylnitrosamine