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. Epub 2015 Mar 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Diabetes Mellitus, Type 2 / complications
  • Drug Evaluation, Preclinical
  • Homeostasis / drug effects
  • Inflammation / chemically induced
  • Inflammation / prevention & control*
  • Ligands
  • Lipopolysaccharides / toxicity*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Molecular
  • Molecular Conformation
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / drug effects*
  • Phenylacetates / pharmacology*
  • Sepsis / drug therapy
  • Sepsis / genetics
  • Transcription Factor RelA / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / drug effects*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Ligands
  • Lipopolysaccharides
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • Transcription Factor RelA
  • n-pentyl 2-(3,5-dihydroxy-2-(1-nonanoyl)phenyl)acetate
  • p38 Mitogen-Activated Protein Kinases