Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages.
Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages.
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发表时间：
1999
影响因子：
4.4
通讯作者：
E. Chan;B. Winston;S. Uh;M. Wynes;D. M. Rose;D. Riches
中科院分区：
文献类型：
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作者：
E. Chan;B. Winston;S. Uh;M. Wynes;D. M. Rose;D. Riches
巨噬细胞诱导型一氧化氮合酶(INOS)的表达受到干扰素-γ和包括肿瘤坏死因子-α在内的多种刺激的刺激。最近的研究表明，肿瘤坏死因子-α可以激活丝裂原活化蛋白激酶家族的成员，进而反式激活参与iNOS表达调控的转录因子。本研究的目的是系统评价p42mapk/ERK2、p46c-jun氨基末端/应激激活蛋白激酶(p46JNK/SAPK)和p38MAPK在干扰素-γ和肿瘤坏死因子-α共刺激小鼠巨噬细胞诱导iNOS表达中的作用。在干扰素-γ和肿瘤坏死因子-α的共刺激作用下，这三种激酶均被激活。而p42mapk/ERK2和p38MAPK分别与PD98059和SKF86002的特异性拮抗对诱导型一氧化氮合酶表达无明显影响。相反，用N-乙酰半胱氨酸阻断这三种酶完全阻断了iNOS表达的诱导。此外，JNK/SAPK上游激酶Mekk(丝裂原活化蛋白激酶/细胞外信号调节激酶)和MKK4(丝裂原活化蛋白激酶4)与显性抑制突变体的特异性拮抗作用阻止了iNOS启动子在与干扰素-γ和肿瘤坏死因子-α共刺激时的转录激活。总之，这些发现支持p46 JNK/SAPK及其上游激酶参与调节在存在干扰素-γ的情况下连接肿瘤坏死因子-α受体CD120a(P55)后诱导型一氧化氮合酶的诱导。
The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma.