Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells:: role of myeloperoxidase
Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells:: role of myeloperoxidase
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DOI：
10.1096/fj.07-8163com
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发表时间：
2007-08-01
期刊：
影响因子：
4.8
通讯作者：
Knaapen, Ad M.
中科院分区：
文献类型：
--
作者：
Gungor, Nejla;Godschalk, Roger W. L.;Knaapen, Ad M.
中性粒细胞被认为通过促进吸入的化学致癌物的代谢，导致前致突变DNA加合物的形成增强，从而影响肺癌的发生。我们假设中性粒细胞通过抑制靶细胞中的核苷酸切除修复（NER）来干扰这种DNA加合物的去除。将人肺泡上皮细胞（A549）与活化的中性粒细胞共培养，我们观察到A549细胞中NER的显著降低，这通过加入髓过氧化物酶（MPO）抑制剂4-氨基苯甲酸酰肼而被废除。MPO产物次氯酸（HOCl）可模拟中性粒细胞的抑制作用，从而引起A549细胞中NER的急性剂量依赖性抑制。这与细胞毒性或ATP损失无关，并持续长达24小时。这些数据得到了支持，显示HOCl引起苯并[ a] pyrenediolepoxide暴露的A549细胞中的DNA加合物的延迟去除。急性HOCl诱导的NER抑制只能部分解释为修复蛋白的氧化修饰。为了解释HOCl更持久的作用，我们分析了NER基因的表达，发现HOCl显著降低XPC表达。总之，这些数据表明，中性粒细胞是核苷酸切除修复的有效抑制剂。这可能为炎症和肺癌发展之间的关联提供进一步的生物学解释。
Neutrophils are thought to affect pulmonary carcinogenesis by promoting the metabolism of inhaled chemical carcinogens, causing enhanced formation of promutagenic DNA adducts. We hypothesized that neutrophils interfere with the removal of such DNA adducts by inhibiting nucleotide excision repair ( NER) in target cells. Human alveolar epithelial cells ( A549) were cocultured with activated neutrophils, and we observed a significant reduction of NER in the A549 cells, which was abrogated by addition of the myeloper-oxidase (MPO) inhibitor 4-aminobenzoic acid hydrazide. The inhibitory effect of neutrophils could be mimicked by the MPO product hypochlorous acid ( HOCl), which caused an acute, dose-dependent inhibition of NER in A549 cells. This was independent of cytotoxicity or ATP loss and persisted up to 24 h. These data were supported by showing that HOCl caused a delayed removal of DNA adducts in benzo[ a] pyrenediolepoxide-exposed A549 cells. The acute HOCl-induced inhibition of NER can only partly be explained by oxidative modification of repair proteins. To explain the more persistent effects of HOCl, we analyzed the expression of NER genes and found that HOCl significantly reduced XPC expression. In conclusion, these data indicate that neutrophils are potent inhibitors of nucleotide excision repair. This may provide a further biological explanation for the association between inflammation and lung cancer development.