One of the enzymes responsible for nitric oxide (NO) production in neutrophils is the inducible nitric oxide synthase (iNOS). Changes in its expression may result from the activation of different signaling pathways, including MAPK, which lead to activation of various genes, including DUSP genes. DUSP induce the negative feedback loop leading to MAPK deactivation through their phosphorylation. Our study assessed the role of DUSP1, DUSP10 and DUSP16 with the participation of MAPK in the iNOS-dependent NO production by neutrophils exposed to xenobiotic, N-nitrosodimethylamine (NDMA). The obtained results suggest that N-nitrosodimethylamine enhances the expression of all tested proteins (except DUSP10) in the cytoplasmic and nuclear fractions of neutrophils. The JNK pathway inhibition resulted in an extenuation of iNOS, phospho-p38 and DUSP10 expression in the cytoplasmic fraction and DUSP1 expression in the nuclear fraction of neutrophils. Inhibition of the p38 pathway led to a lower expression of iNOS, DUSP16 and DUSP10 in the cytoplasmic fraction. No changes in the phospho-JNK and DUSP1 expressions were observed. With the results of this study we can conclude that DUSP are positive regulators of MAP kinases in NDMA-induced signaling pathway which lead to modulation of iNOS-dependent NO production in human neutrophils.

中文翻译：

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MAPK双特异性磷酸酶（DUSP）在暴露于N-亚硝基二甲胺的人中性粒细胞中对NO产生的调节

导致中性粒细胞产生一氧化氮（NO）的酶之一是诱导型一氧化氮合酶（iNOS）。其表达的变化可能是由包括MAPK在内的不同信号通路的激活导致的，后者导致了包括DUSP基因在内的各种基因的激活。DUSP通过其磷酸化诱导负反馈回路，导致MAPK失活。我们的研究评估了DUSP1，DUSP10和DUSP16在MAPK参与异源生物，N-亚硝基二甲胺（NDMA）接触的中性粒细胞产生iNOS依赖性NO产生中的作用。获得的结果表明，N-亚硝基二甲胺可增强嗜中性粒细胞胞质和核级分中所有测试蛋白质（DUSP10除外）的表达。JNK途径的抑制导致iNOS的延长，嗜中性粒细胞的胞质部分中的磷酸化p38和DUSP10表达，中性粒细胞的核部分中的DUSP1表达。p38途径的抑制导致iNOS，DUSP16和DUSP10在细胞质级分中的较低表达。没有观察到磷酸化JNK和DUSP1表达的变化。根据这项研究的结果，我们可以得出结论，DUSP是NDMA诱导的信号传导途径中MAP激酶的正调节剂，可调节人嗜中性粒细胞中iNOS依赖性NO的产生。