4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells
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DOI：
10.1111/j.1365-2249.2005.02739.x
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发表时间：
2005-04-01
影响因子：
4.6
通讯作者：
Bissonnette, ÉY
中科院分区：
文献类型：
--
作者：
Proulx, LI;Gaudreault, M;Bissonnette, ÉY
呼吸道上皮细胞通过释放介质参与免疫应答。本研究的目的是表征烟草致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）对呼吸道上皮细胞的免疫调节作用，并使用选择性前体4-（乙酰氧基-甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNKOAc）和n -亚硝基（乙酰氧基甲基）甲胺（NDMAOAc）比较两种代谢途径，α -甲基羟化和α -亚甲基羟化，分别参与这些作用。用NNK、NNKOAc和NDMAOAc分别处理人支气管和肺泡上皮细胞系BEAS-2B和A549 24 h，加瘤坏死因子（TNF）和不加肿瘤坏死因子（TNF），用酶联免疫吸附试验（ELISA）检测无细胞上清中释放的介质。NNK显著抑制两种细胞类型的白细胞介素(IL)-8、IL-6和单核细胞趋化蛋白-1 （MCP-1）的产生。原代支气管和肺泡上皮细胞也观察到类似的结果。虽然NNK增加了A549细胞的前列腺素E-2 （PGE(2)）的产生，但根据环加氧酶抑制剂的结果，其免疫调节作用不是由PGE(2)介导的。NNKOAc模拟NNK效应，而NDMAOAc显著抑制BEAS-2B细胞和两种细胞类型MCP-1中IL-8的产生。这些结果表明，NNK及其反应性代谢物对呼吸道上皮细胞具有免疫抑制作用，这可能有助于吸烟者呼吸道感染的增加以及肺癌的发生和/或进展。
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.