Orphan nuclear receptor Nur77 inhibits poly (I:C)-triggered acute liver inflammation by inducing the ubiquitin-editing enzyme A20.
Orphan nuclear receptor Nur77 inhibits poly (I:C)-triggered acute liver inflammation by inducing the ubiquitin-editing enzyme A20.
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孤儿核受体 Nur77 通过诱导泛素编辑酶 A20 抑制聚 (I:C) 引发的急性肝脏炎症
DOI：
10.18632/oncotarget.17731
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Li XM;Yang TY;He XS;Wang JR;Gan WJ;Zhang S;Li JM;Wu H
炎症是各种类型的急性和慢性肝病的关键因素。我们最近报道，缺乏Nur 77，孤儿核受体，有助于炎症性疾病，包括炎症性肠病和败血症的发病机制。然而，Nur 77是否在肝脏炎症中起关键作用仍有待充分了解。在野生型（Nur 77 +/+）和Nur 77-/-小鼠中采用体内急性肝脏炎症模型，我们发现Nur 77缺乏显著增加了Nur 77-/-小鼠中促炎细胞因子的产生，并加速了poly（I：C）/D-GalN诱导的肝损伤。Nur 77通过诱导泛素编辑酶A20（Nur 77的新靶基因）的表达，作为NF-κB信号传导的负调节剂。值得注意的是，在炎症细胞中，A20的过表达增强了Nur 77对poly（I：C）触发的炎症的抑制作用，而通过siRNA方法敲低A20则削弱了Nur 77对poly（I：C）触发的炎症的抑制作用。总的来说，我们的数据表明孤儿核受体Nur 77通过诱导A20在poly（I：C）触发的肝脏炎症中起保护作用，从而使其成为预防和治疗肝脏炎症的有希望的靶点。
Inflammation is a key contributor to various types of acute and chronic liver disease. We recently reported that lack of Nur77, an orphan nuclear receptor, contributes to the pathogenesis of inflammatory diseases including inflammatory bowel disease and sepsis. However, whether Nur77 plays a critical role in liver inflammation remains to be fully understood. Employing in vivo acute liver inflammation model in wild-type (Nur77+/+) and Nur77-/- mice, we here found that Nur77 deficiency dramatically increased the production of pro-inflammatory cytokines and accelerated liver injury induced by poly (I:C)/D-GalN in Nur77-/- mice. Mechanistically, Nur77 acts as a negative regulator of NF-κB signaling by inducing the expression of ubiquitin-editing enzyme A20, a novel target gene of Nur77. Notably, in inflammatory cells, overexpression of A20 enhanced, whereas knockdown of A20 by siRNA approach impaired, the inhibitory effect of Nur77 on poly (I:C)-triggered inflammation. Collectively, our data suggest that the orphan nuclear receptor Nur77 plays a protective role in poly (I:C)-triggered liver inflammation by inducing A20, thus making it a promising target for the prevention and treatment of liver inflammation.
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