ISG12 is a critical modulator of innate immune responses in murine models of sepsis.
ISG12 is a critical modulator of innate immune responses in murine models of sepsis.
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DOI：
10.1016/j.imbio.2013.04.009
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发表时间：
2013-09
期刊：
影响因子：
2.8
通讯作者：
Schabbauer, G.
中科院分区：
文献类型：
--
作者：
Uhrin, P.;Perkmann, T.;Binder, B.;Schabbauer, G.
脓毒症每年的发病率和死亡率都很高，是社会的一大负担。与脓毒症相关的全身炎症反应综合征（SIRS）的分子机制仍然不明确，大多数针对疾病的急性炎症成分的治疗方法都不充分。最近，核受体（NRs）的作用成为炎症过程中转录调控的一个主要研究课题。核受体，如过氧化物酶体增殖物激活受体（PPARs），已被证明通过干扰NFκB通路发挥抗炎特性。我们确定了核膜蛋白，干扰素刺激基因12（ISG 12），它直接与核受体相互作用。ISG 12是刺激NR的核输出的辅因子，从而降低NR如NR 4A 1的抗炎潜力。为了检查ISG 12在急性炎症过程中的作用，我们使用了最近产生的ISG 12缺陷小鼠。我们可以清楚地证明，缺乏ISG 12在实验性脓毒症和内毒素血症中降低存活率。此外，我们可以证明，一些急性炎症参数，如全身IL 6细胞因子水平，在脓毒症ISG 12 −/−动物中下调。因此，在源自ISG 12缺陷型小鼠的腹腔巨噬细胞的体外实验中获得了类似的结果。相反，核受体NR 4A 1缺陷的小鼠表现出加剧的先天免疫应答，并在致死性内毒素血症攻击后显示出显著更高的死亡率。这种显著的表型可以在ISG 12/NR 4A 1双缺陷小鼠中恢复。我们从我们的体外和体内数据中得出结论，ISG 12是调节抗炎核受体如NR 4A 1的先天免疫应答的新型调节剂。
Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been demonstrated to exert anti-inflammatory properties by interfering with the NFκB pathway. We identified the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. To examine the role of ISG12 in acute inflammatory processes we used recently generated ISG12 deficient mice. We can clearly demonstrate that lack of ISG12 prolongs survival in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12−/− animals. Consistently, similar results were obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1.
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