title: Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.
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.
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Hang-zi
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Feng-wei
authors.initials: FW
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jian-feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Hong-kui
authors.initials: HK
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: He
authors.affiliation: 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.
authors.forename: Yong-zhen
authors.initials: YZ
authors.lastname: Xing
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wei-jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xu-yang
authors.initials: XY
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: An-zhong
authors.initials: AZ
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
authors.forename: Pei-qiang
authors.initials: PQ
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004353:Drug Evaluation, Preclinical; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000187:drug effects*; D010648:Phenylacetates / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D008070:Lipopolysaccharides; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; D051996:Transcription Factor RelA; C000598886:n-pentyl 2-(3,5-dihydroxy-2-(1-nonanoyl)phenyl)acetate; D048051:p38 Mitogen-Activated Protein Kinases
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