title: Alveolar macrophage cytotoxic activity is inhibited by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic component of cigarette smoke.
abstract: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a carcinogenic compound of cigarette smoke that generates electrophilic intermediates capable of damaging DNA. Recently, we have shown that NNK can modulate mediator production by alveolar macrophages (AM) and bronchial and alveolar epithelial cells, suggesting that cigarette smoke can alter lung immune response. Thus, we investigated the effect of NNK and cigarette smoke extract (CSE) on AM capacity to eliminate tumoral cells. Rat AM cell line, NR8383, was treated with NNK (500 microM) or CSE (3%) and stimulated with lipopolysaccharide (10 ng/ml). The release of cytotoxic mediators, tumor necrosis factor (TNF) and reactive oxygen species (ROS), was measured in cell-free supernatants using ELISA and superoxide anion production. TNF- and ROS-dependent cytotoxicity were studied using a (51)Chromium-release assay and WEHI-164 and P-815 cell lines. Treatment of AM with NNK and CSE for 18 h significantly inhibited AM TNF release. CSE exposure resulted in a significant increase of ROS production, whereas NNK did not. TNF-dependent cytotoxic activity of NR8383 and freshly isolated rat AM was significantly inhibited after treatment with NNK and CSE. Interestingly, although ROS production was stimulated by CSE and not affected by NNK, CSE inhibited AM ROS-dependent cytotoxicity. These results suggest that NNK may be one of the cigarette smoke components responsible for the reduction of pulmonary cytotoxicity. Thus, NNK may have a double pro-carcinogenic effect by contributing to DNA adduct formation and inhibiting AM cytotoxicity against tumoral cells.
authors.affiliation: Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, 2725 Chemin Ste-Foy, G1V 4G5 Quebec, QC, Canada.
authors.forename: Léa-Isabelle
authors.initials: LI
authors.lastname: Proulx
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.forename: Elyse Y
authors.initials: EY
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000276:immunology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D017382:Reactive Oxygen Species; D014028:Tobacco Smoke Pollution; D014409:Tumor Necrosis Factor-alpha; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone