Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the jun N-terminal kinase
Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the jun N-terminal kinase
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DOI：
10.1124/mol.106.033449
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发表时间：
2007-05-01
影响因子：
3.6
通讯作者：
Kleinert, Hartmut
中科院分区：
文献类型：
--
作者：
Korhonen, Riku;Linker, Katrin;Kleinert, Hartmut
人类诱导型一氧化氮合酶 (iNOS) 表达在转录和转录后水平上受到调节。在本研究中，研究了 Jun N 末端激酶 (JNK) 对人类 iNOS 表达的影响。在 A549/8 人肺泡上皮细胞中，药理学抑制剂 anthra[1,9-cd]pyrazol-6(2H)-one1,9-pyrazoloanthrone (SP600125) 对 JNK 的抑制以及小干扰 RNA (siRNA) 介导的 JNK 下调均导致 iNOS mRNA 和蛋白质表达减少。 iNOS 启动子活性不受这些治疗的影响。因此，JNK 似乎通过稳定 iNOS mRNA 的转录后机制来调节 iNOS 表达。我们的实验室最近表明，细胞因子诱导的 RNA 结合蛋白 tristetraprolin (TTP) 通过稳定 iNOS mRNA 是人类 iNOS 表达的主要正调节因子。因此，研究了SP600125抑制JNK或siRNA下调对TTP表达的影响。 SP600125 和靶向 JNK 的 siRNA 均导致 TTP 蛋白表达减少，但不影响 TTP mRNA 的量。这些数据表明 JNK 对 TTP 表达进行转录后控制。此外，SP600125 或 siRNA 对 JNK 信号传导的调节不会改变 p38 磷酸化。总之，结果表明 JNK 可能通过 TTP 依赖性机制稳定 iNOS mRNA 来调节人 iNOS 表达。
Human inducible nitric-oxide synthase (iNOS) expression is regulated both at transcriptional and post-transcriptional levels. In the present study, the effect of Jun N-terminal kinase (JNK) on human iNOS expression was investigated. In A549/8 human alveolar epithelial cells, both the inhibition of JNK by a pharmacological inhibitor anthra[1,9-cd]pyrazol- 6(2H)- one1,9-pyrazoloanthrone (SP600125) and small interfering RNA (siRNA)mediated down-regulation of JNK led to a reduction of iNOS mRNA and protein expression. iNOS promoter activity was not affected by these treatments. Hence, JNK seems to regulate iNOS expression through post-transcriptional mechanisms by stabilizing iNOS mRNA. Our laboratory has shown recently that a cytokine-induced RNA binding protein tristetraprolin (TTP) is a major positive regulator of human iNOS expression by stabilizing iNOS mRNA. Therefore, the effect of JNK inhibition by SP600125 or down-regulation by siRNA on TTP expression was investigated. Both SP600125 and siRNA targeted at JNK resulted in a reduction of TTP protein expression without affecting the amount of TTP mRNA. These data suggest a post-transcriptional control of TTP expression by JNK. Moreover, the modulation of JNK signaling by SP600125 or siRNA did not change p38 phosphorylation. In summary, the results suggest that JNK regulates human iNOS expression by stabilizing iNOS mRNA possibly by a TTP-dependent mechanism.