| First Author | Li L | Year | 2015 |
| Journal | Nat Chem Biol | Volume | 11 |
| Issue | 5 | Pages | 339-46 |
| PubMed ID | 25822914 | Mgi Jnum | J:247470 |
| Mgi Id | MGI:5927454 | Doi | 10.1038/nchembio.1788 |
| Citation | Li L, et al. (2015) Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat Chem Biol 11(5):339-46 |
| abstractText | 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-kappaB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the kappaB element. However, this function of Nur77 is countered by the LPS-activated p38alpha phosphorylation of Nur77. Dampening the interaction between Nur77 and p38alpha 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-p38alpha interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-kappaB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38alpha substrate to modulate p38alpha-regulated functions. |
