The
nicotine-derived N-
nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is one of the most abundant and potent
carcinogens found in tobacco
smoke. NNK induces lung
tumors in rodents and is most likely involved in lung
carcinogenesis in humans. Studies on the metabolism and carcinogenicity of NNK have been extensive. However, its effects on the immune system have not been investigated thoroughly. Considering that tobacco smoking partially suppresses the immune response in humans, and that immune surveillance plays a critical role in
cancer development, we examined the effects of NNK on the production of selected
cytokines. In a previous study, we observed an inhibition of NK cell activity and
IgM secretory cell number in NNK-treated A/J mice [Rioux and Castonguay (1997) J Natl
Cancer Inst 89: 874]. In this study, we demonstrate that U937 human macrophages activate NNK to alkylating intermediates by alpha-
carbon hydroxylation and detoxify NNK by N-oxidation. We observed that NNK, following activation, induces the release of soluble
tumor necrosis factor (TNF), but inhibits interleukin(IL)-10 synthesis. We also report that 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)- -butanone, and nitroso(acetoxymethyl)
methylamine, which generate the same alkylating intermediates as NNK, have similar effects on TNF and
IL-10. This suggests that pyridyloxobutylating and methylating intermediates generated from NNK are potent modulators of the immune response. The levels of
IL-6,
granulocyte/macrophage-colony-stimulating factor and macrophage chemotactic
protein 1 were also decreased in supernatants of NNK-treated U937 macrophages. In contrast,
IL-2 synthesis in Jurkat cells was inhibited by NNK treatment. This is the first study demonstrating that NNK, via its alkylating intermediates, alters the
cytokine synthesis profile in human cells. Modulation of
cytokine synthesis by NNK might partially explain the immunosuppresion observed in smokers. Inhibition of immune functions, resulting from NNK activation to
alkylating agents, may facilitate lung
tumor development.