4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone modulation of cytokine release in U937 human macrophages

The nicotine-derived N-nitrosamine, 4-(methylnitrosamino)- 1-(3-pyridyl)- 1 -butanone (NNK), is one of the most abundant and potent carcinogens found i n tobacco smoke. NNK induces lung tumors in rodents and is most likely invo lved in lung carcinogenesis in humans. Studies on the metabolism and carcin ogenicity of NNK have been extensive. However, its effects on the immune sy stem have not been investigated thoroughly. Considering that tobacco smokin g partially suppresses the immune response in humans, and that immune surve illance plays a critical role in cancer development, we examined the effect s of NNK on the production of selected cytokines. In a previous study, we o bserved 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 a-carbon hydroxylation and detoxify NNK by N-o xidation. We observed that NNK. following activation, induces the release o f soluble tumor necrosis factor (TNF), but inhibits interleukin(IL)-10 synt hesis. We also report that 4-(acetoxymethylnitrosamino)- 1-(3-pyridyl)-1 -b utanone, and nitroso(acetoxymethyl)methylamine, which generate the same alk ylating intermediates as NNK, have similar effects on TNF and IL-10. This s uggests that pyridyloxobutylating and methylating intermediates generated f rom NNK are potent modulators of the immune response. The levels of IL-6, g ranulocyte/macrophage-colony-stimulating factor and macrophage chemotactic protein 1 were also decreased in supernatants of NNK-treated U937 macrophag es. In contrast, IL-2 synthesis in Jurkat cells was inhibited by NNK treatm ent. This is the first study demonstrating that NNK, via its alkylating int ermediates, alters the cytokine synthesis profile in human cells. Modulatio n of cytokine synthesis by NNK might partially explain the immunosuppresion observed in smokers. Inhibition of immune functions, resulting from NNK ac tivation to alkylating agents, may facilitate lung tumor development.