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首页> 外文期刊>APMIS: Acta Pathologica, Microbiologica et Immunologica Scandinavica >Effect of N-nitrosodimethylamine on inducible nitric oxide synthase expression and production of nitric oxide by neutrophils and mononuclear cells: the role of JNK signalling pathway.
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Effect of N-nitrosodimethylamine on inducible nitric oxide synthase expression and production of nitric oxide by neutrophils and mononuclear cells: the role of JNK signalling pathway.

机译：N-亚硝基二甲胺对中性粒细胞和单核细胞诱导型一氧化氮合酶表达和一氧化氮产生的影响：JNK信号通路的作用。

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摘要

In neutrophils (PMN) and mononuclear cells (PBMC), one of the enzymes responsible for nitric oxide (NO) synthesis is inducible nitric oxide synthase (iNOS). Changes in iNOS expression result from various signalling pathways including the mitogen-activated protein kinase (MAPK) pathway activated by endogenic and exogenic factors. N-nitrosodimethylamine (NDMA) is a xenobiotic with widespread occurrence in human environment and has an effect on cells of the immune system. The aim of this study was to determine the effect of NDMA on iNOS expression and NO production by human PMN and PBMC cells in the light of superoxide anion production by PMN cells. Moreover, the role of JNK and p38 pathways in NO production with involvement of iNOS was studied. Additionally, the function of JNK pathway in generation of superoxide anion was determined. Moreover, nitrotyrosine expression was studied in PMN and PBMC cells in the presence of NDMA. This work shows that NDMA increases iNOS expression and NO production by PMN and PBMC cells. In addition, elevated expression of phospho-JNK and phospho-p38, which are markers of JNK and p38 MAPK pathways activation, were observed. Lower iNOS expression and NO production by neutrophils exposed to extended action of NDMA were observed after application of inhibitor of JNK and p38 pathways. Lower phospho-p38 expression in PMN stimulated by NDMA was found as a result of arresting JNK pathway, whereas, application of inhibitor of p38 pathway resulted in enhanced phospho-JNK expression in PMN and PBMC cells. Increased ability to release superoxide anion by NDMA-stimulated PMN cells was observed. This ability was reduced after the application of inhibitor of JNK pathway. In PMN and PBMC cells exposed to NDMA, an increased expression of nitrotyrosine, which is dependant on JNK and p38 pathways that are activated by this particular xenobiotic, was observed. Generally, increased induction of iNOS related to elevated production of NO by PMN and PBMC cells exposed to NDMA may result in dysfunction of regulation of immunity responses controlled by this molecule in various conditions. Increased expression of nitrotyrosine in PMN and PBMC cells exposed to NDMA may affect their functions in an auto- and/or a paracrine way. Mutual interactions of JNK and p38 MAPK during the induction of iNOS expression in cells exposed to NDMA indicate complex mechanism of induction of iNOS synthase.
机译：在中性粒细胞（PMN）和单核细胞（PBMC）中，负责一氧化氮（NO）合成的酶之一是诱导型一氧化氮合酶（iNOS）。 iNOS表达的变化是由多种信号通路引起的，包括被内源性和外源性因子激活的丝裂原激活的蛋白激酶（MAPK）通路。 N-亚硝基二甲胺（NDMA）是在人类环境中广泛存在的异种生物，对免疫系统的细胞有影响。这项研究的目的是根据PMN细胞产生的超氧阴离子来确定NDMA对人PMN和PBMC细胞iNOS表达和NO产生的影响。此外，还研究了iNOS参与下JNK和p38途径在NO产生中的作用。另外，确定了JNK途径在超氧阴离子产生中的功能。此外，在存在NDMA的情况下研究了PMN和PBMC细胞中硝基酪氨酸的表达。这项工作表明NDMA增加了PMN和PBMC细胞的iNOS表达和NO产生。另外，观察到磷酸化JNK和磷酸化p38的表达升高，这是JNK和p38 MAPK途径激活的标志。应用JNK和p38途径抑制剂后，观察到暴露于NDMA扩展作用的中性粒细胞的iNOS表达降低，NO生成减少。发现NDMA刺激的PMN中磷酸化p38表达降低是由于JNK途径的阻滞，而p38途径抑制剂的应用导致PMN和PBMC细胞中磷酸化JNK表达的增强。观察到NDMA刺激的PMN细胞释放超氧阴离子的能力增强。应用JNK途径抑制剂后，这种能力降低。在暴露于NDMA的PMN和PBMC细胞中，观察到硝基酪氨酸的表达增加，该酪氨酸依赖于由该特定异源物质激活的JNK和p38途径。通常，与暴露于NDMA的PMN和PBMC细胞升高的NO产生有关的iNOS诱导作用增加，可能导致在各种情况下该分子控制的免疫应答的调节功能失调。在暴露于NDMA的PMN和PBMC细胞中，硝基酪氨酸的表达增加可能会以自分泌和/或旁分泌方式影响其功能。在暴露于NDMA的细胞中诱导iNOS表达期间，JNK和p38 MAPK的相互作用表明了诱导iNOS合酶的复杂机制。

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