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首页> 外文期刊>Cellular Signalling >Requirement of heat shock protein 70 for inducible nitric oxide synthase induction
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Requirement of heat shock protein 70 for inducible nitric oxide synthase induction

机译：热休克蛋白70诱导型一氧化氮合酶诱导的要求

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Inducible nitric oxide synthase (iNOS) contributes critically to inflammation and host defense. While normally undetectable, iNOS expression is induced by endotoxins and cytokines via discrete signaling pathways. Lipopolysaccharide (LPS) triggers iNOS gene transactivation by the IKK-NF-κB cascade, whereas interferon-γ (IFN-γ) acts through transcriptional factor STAT1 and IRF-1. Previous studies showed that heat shock protein 90 is essential for iNOS gene transactivation. But the role of the closely related heat shock protein 70 (Hsp70) in iNOS induction remains unknown. We address this issue in cultured cells and endotoxemic mice. With mouse macrophages, Hsp70 inhibition or knockdown prevented LPS/IFN-γ-stimulated iNOS protein expression. RT-PCR experiments showed that both LPS- and IFN-γ-induced iNOS mRNA transcriptions were blocked by Hsp70 inhibitor. The preventing effect of Hsp70 inhibition on iNOS gene transcription was confirmed in vivo in endotoxemic mice. Further studies revealed that Hsp70 inhibition disabled IKK activation in LPS-stimulated cells, hence precluding NF-κB-initiated iNOS gene transcription. Intriguingly, Hsp70 inhibition had little effect on IFN-γ-elicited STAT1 activation or IRF-1 upregulation. But ChIP assays showed that both STAT1 and IRF-1 bindings to iNOS promoters were markedly reduced in Hsp70-inhibited cells. Hsp70 inhibition had no significant effect on iNOS mRNA stability. These studies uncover the necessity of Hsp70 for iNOS induction. Hsp70 is required for IKK activation and STAT1/IRF-1 promoter binding amid iNOS gene transactivation. Selectively targeting Hsp70 may be a new approach to intervene iNOS expression in diseases.
机译：诱导型一氧化氮合酶（iNOS）对炎症和宿主防御至关重要。尽管通常无法检测到，但iNOS表达是由内毒素和细胞因子通过离散的信号传导途径诱导的。脂多糖（LPS）通过IKK-NF-κB级联触发iNOS基因反式激活，而干扰素-γ（IFN-γ）通过转录因子STAT1和IRF-1起作用。先前的研究表明，热激蛋白90对于iNOS基因的反式激活至关重要。但是，密切相关的热休克蛋白70（Hsp70）在iNOS诱导中的作用仍然未知。我们在培养的细胞和内毒素血症小鼠中解决了这个问题。对于小鼠巨噬细胞，Hsp70抑制或敲低阻止了LPS /IFN-γ刺激的iNOS蛋白表达。 RT-PCR实验表明，LPS和IFN-γ诱导的iNOS mRNA转录均被Hsp70抑制剂阻断。在内毒素血症小鼠体内证实了Hsp70抑制对iNOS基因转录的预防作用。进一步的研究表明，Hsp70抑制作用会抑制LPS刺激的细胞中的IKK活化，因此排除了NF-κB引发的iNOS基因转录。有趣的是，Hsp70抑制作用对IFN-γ引起的STAT1激活或IRF-1上调几乎没有影响。但是ChIP分析表明，在Hsp70抑制的细胞中，STAT1和IRF-1与iNOS启动子的结合均显着降低。 Hsp70抑制对iNOS mRNA稳定性无明显影响。这些研究揭示了Hsp70诱导iNOS的必要性。在iNOS基因反式激活过程中，IKK激活和STAT1 / IRF-1启动子结合需要Hsp70。选择性靶向Hsp70可能是一种干预iNOS在疾病中表达的新方法。

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