2. Academic Validation
  3. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

  • Nat Chem Biol. 2015 May;11(5):339-46. doi: 10.1038/nchembio.1788.
Li Li 1,  Yuan Liu 1,  Hang-zi Chen 1,  Feng-wei Li 1,  Jian-feng Wu 1,  Hong-kui Zhang 2,  Jian-ping He 1,  Yong-zhen Xing 1,  Yan Chen 1,  Wei-jia Wang 1,  Xu-yang Tian 1,  An-zhong Li 1,  Qian Zhang 1,  Pei-qiang Huang 2,  Jiahuai Han 1,  Tianwei Lin 1,  Qiao Wu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
  • 2 Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
PMID: 25822914 DOI: 10.1038/nchembio.1788
Abstract

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-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α 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-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

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