title: Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages.
abstract: Lung cancer is strongly associated with cigarette smoking. More than 20 lung carcinogens have been identified in cigarette smoke and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We hypothesized that NNK modulates alveolar macrophage (AM) mediator production, thus contributing to carcinogenesis. An AM cell line, NR8383, was treated with [3H]NNK and lipopolysaccharide (LPS), and NNK metabolites released in supernatants were analysed by high-performance liquid chromatography (HPLC). NNK was metabolized by carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol (NNAL) or activated by alpha-carbon hydroxylation. AMs were also treated with NNK (100-1000 micro M), with and without LPS, for different periods of time (6-72 h), and mediators released in supernatants were quantified by enzyme-linked immunosorbent assay (ELISA) or the Griess reaction. NNK inhibited (in a concentration-dependent manner) AM production of tumour necrosis factor (TNF), macrophage inflammatory protein-1alpha (MIP-1alpha), interleukin (IL)-12 and nitric oxide (NO), whereas IL-10 production was increased. Cyclooxygenase inhibitors - NS-398 and indomethacin - and anti-prostaglandin E2 (anti-PGE2) antibody abrogated the NNK-inhibitory effect on MIP-1alpha production by AM. NNK stimulated the release of PGE2, and exogenous PGE2 inhibited AM MIP-1alpha production, suggesting that the NNK immunomodulatory effect may be mediated by PGE2 production. Thus, in addition to its carcinogenic effects, NNK may contribute to the lung immunosuppression observed in tobacco smokers.
authors.affiliation: Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Ste-Foy, Québec, Canada.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Therriault
authors.forename: L-I
authors.initials: LI
authors.lastname: Proulx
authors.forename: A
authors.initials: A
authors.lastname: Castonguay
authors.forename: E Y
authors.initials: EY
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003864:Depression, Chemical; D015232:Dinoprostone / Q000096:biosynthesis / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D002273:Carcinogens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D009578:Nitrobenzenes; D009602:Nitrosamines; D011725:Pyridines; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol; D015232:Dinoprostone; D007213:Indomethacin