Rioux N, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada.
Cancer Immunol Immunother. 2001 Feb;49(12):663-70. doi: 10.1007/s002620000157.
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.
尼古丁衍生的N-亚硝胺，4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK），是烟草烟雾中含量最丰富且最具致癌性的物质之一。NNK可在啮齿动物中诱发肺肿瘤，很可能也与人类肺癌的发生有关。关于NNK代谢和致癌性的研究已经很广泛。然而，其对免疫系统的影响尚未得到充分研究。鉴于吸烟会部分抑制人类的免疫反应，且免疫监视在癌症发展中起关键作用，我们研究了NNK对特定细胞因子产生的影响。在之前的一项研究中，我们观察到经NNK处理的A/J小鼠的自然杀伤（NK）细胞活性和IgM分泌细胞数量受到抑制[Rioux和Castonguay（1997年），《美国国家癌症研究所杂志》89：874]。在本研究中，我们证明U937人巨噬细胞通过α-碳羟基化将NNK激活为烷基化中间体，并通过N-氧化对NNK进行解毒。我们观察到，激活后的NNK会诱导可溶性肿瘤坏死因子（TNF）的释放，但会抑制白细胞介素（IL）-10的合成。我们还报告称，4-（乙酰氧基甲基亚硝胺基）-1-（3-吡啶基）-丁酮和亚硝基（乙酰氧基甲基）甲胺，它们产生与NNK相同的烷基化中间体，对TNF和IL-10有类似影响。这表明NNK产生的吡啶氧基丁基化和甲基化中间体是免疫反应的有效调节剂。在经NNK处理的U937巨噬细胞的上清液中，IL-6、粒细胞/巨噬细胞集落刺激因子和巨噬细胞趋化蛋白1的水平也有所降低。相反，经NNK处理会抑制Jurkat细胞中IL-2的合成。这是第一项证明NNK通过其烷基化中间体改变人类细胞中细胞因子合成谱的研究。NNK对细胞因子合成的调节可能部分解释了吸烟者中观察到的免疫抑制现象。NNK激活为烷基化剂导致的免疫功能抑制可能会促进肺肿瘤的发展。
