Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation
Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation
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阻碍 nur77 和 p38 之间的相互作用可减少 Lps 诱导的炎症
DOI：
10.1038/nchembio.1788
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发表时间：
2015-05-01
影响因子：
14.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Li, Li;Liu, Yuan;Wu, Qiao
脓毒症是一种可导致多器官功能障碍的高炎症反应，是感染致死的主要原因。在这里，我们发现孤儿核受体Nur77（也称为TR3）可以通过抑制nf - κ B活性和抑制异常细胞因子的产生来增强小鼠对脂多糖（LPS）诱导的脓毒症的抵抗力。Nur77直接与p65结合，阻断其与kappa B元件的结合。然而，Nur77的这种功能被lps激活的p38 α磷酸化所抵消。抑制Nur77和p38 α之间的相互作用有利于Nur77抑制高炎症反应。从nur77偏向文库中筛选到一个化合物n-戊基2-[3,5-二羟基-2-（1-壬烷基）苯基]醋酸酯，通过靶向Nur77的配体结合域阻断Nur77-p38 α相互作用，并通过Nur77抑制NF-kappa b恢复对高炎症反应的抑制。这项研究将核受体与免疫稳态联系起来，并暗示了一种新的治疗策略，即通过靶向p38 α底物来调节p38 α调节的功能来治疗高炎症反应。
Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-kappa B activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the kappa B element. However, this function of Nur77 is countered by the LPS-activated p38 alpha phosphorylation of Nur77. Dampening the interaction between Nur77 and p38 alpha would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38 alpha interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-kappa B. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38 alpha substrate to modulate p38 alpha-regulated functions.