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.