NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis
NUR77 exerts a protective effect against inflammatory bowel disease by negatively regulating the TRAF6/TLR-IL-1R signalling axis
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NUR77 通过负向调节 TRAF6/TLR-IL-1R 信号轴发挥针对炎症性肠病的保护作用
DOI：
10.1002/path.4670
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发表时间：
2016-02-01
影响因子：
7.3
通讯作者：
Li, Jian-Ming
中科院分区：
文献类型：
--
作者：
Wu, Hua;Li, Xiu-Ming;Li, Jian-Ming
Nur 77是一个立即早期反应基因，参与广泛的生物学功能。其人类同源物NUR 77有几个名称，并具有HGNC批准的基因符号NR 4A 1。然而，Nur 77在炎症性肠病（IBD）中的作用及其潜在机制仍然难以捉摸。在这里，使用国际炎症性肠病遗传学联盟（IIBDGC）关于溃疡性结肠炎（UC）和克罗恩病（CD）的最新全基因组关联研究（GWAS）的公开数据，我们发现E77基因的遗传变异与UC和CD的风险增加相关。因此，在来自UC或CD患者和用DSS治疗的小鼠的结肠组织中，Nur 77表达显著降低。Nur 77缺乏增加了小鼠对DSS诱导的实验性结肠炎的易感性，并阻止了肠道恢复，而用Nur 77的激动剂细胞孢素B（Csn-B）治疗显著减弱了DSS诱导的结肠炎小鼠模型中的过度炎症反应。从机制上讲，TLR 77通过与TRAF 6相互作用作为TLR-IL-1 R信号传导的负调节剂。这种相互作用阻止TRAF 6的自身泛素化和寡聚化，随后抑制NF-B活化和促炎细胞因子产生。总之，我们基于GWAS的分析以及体外和体内研究表明，Nur 77是TRAF 6/TLR-IL-1 R启动的炎症信号传导的重要调节因子，Nur 77的缺失可能有助于IBD的发展，这表明Nur 77是预防和治疗IBD的潜在靶点。版权所有（c）2015大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-B activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.