Evaluation of the Role of Mitogen-Activated Protein Kinases in the Expression of Inducible Nitric Oxide Synthase by IFN-γ and TNF-α in Mouse Macrophages
Evaluation of the Role of Mitogen-Activated Protein Kinases in the Expression of Inducible Nitric Oxide Synthase by IFN-γ and TNF-α in Mouse Macrophages
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DOI：
10.4049/jimmunol.162.1.415
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发表时间：
1999-01
期刊：
影响因子：
--
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
巨噬细胞表达诱导型一氧化氮合酶 (iNOS) 会受到 IFN-γ 和多种刺激物（包括 TNF-α）的共同暴露的刺激。最近的研究表明，TNF-α 激活丝裂原激活蛋白激酶家族的成员，随后反式激活参与 iNOS 表达调节的转录因子。本研究的目的是系统评估以下因素的作用：1) p42mapk/erk2、2) p46 c-Jun NH2 末端激酶/应激激活蛋白激酶 (p46 JNK/SAPK) 和 3) p38mapk 在用 IFN-γ 和 TNF-α 共刺激小鼠巨噬细胞期间诱导 iNOS 表达中的作用。所有三种激酶在 IFN-γ 和 TNF-α 共刺激过程中均被激活。然而，p42mapk/erk2 和 p38mapk 分别与 PD98059 和 SKF86002 的特异性拮抗作用对 iNOS 表达的诱导没有影响。相反，用 N-乙酰半胱氨酸阻断所有三种激酶完全阻断 iNOS 表达的诱导。此外，具有显性抑制突变体的 JNK/SAPK 上游激酶 MEKK（丝裂原激活蛋白激酶/细胞外信号调节激酶激酶）和 MKK4（丝裂原激活蛋白激酶激酶 4）的特异性拮抗作用，可阻断 iNOS 启动子响应 IFN-γ 和 TNF-α 共刺激的转录激活。总的来说，这些发现支持 p46 JNK/SAPK 及其上游激酶在 IFN-γ 存在下连接 TNF-α 受体 CD120a (p55) 后参与调节 iNOS 的诱导。
The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-γ and a number of stimuli, including TNF-α. Recent work has shown that TNF-α 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-γ and TNF-α. All three kinases were activated during costimulation with IFN-γ and TNF-α. 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-γ and TNF-α. 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-α receptor CD120a (p55) in the presence of IFN-γ.