4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone modulation of cytokine release in U937 human macrophages |
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Authors: | N Rioux A Castonguay |
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Institution: | (1) Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada G1 K 7P4 e-mail: andre.castonguay@pha.ulaval.ca Tel.: +1-418-656-2131 Ext. 3182 Fax: +1-418-656-2305, CA |
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Abstract: | 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 α-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)-1-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.
Received: 3 February 2000 / Accepted: 15 September 2000 |
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Keywords: | Nitrosamine Cytokines Macrophages Tobacco |
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