title: TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.
abstract: Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-κB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, PR China.
authors.forename: X-F
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: P-X
authors.initials: PX
authors.lastname: Wang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: D-S
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: L-H
authors.initials: LH
authors.lastname: Zhu
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: S
authors.initials: S
authors.lastname: Tian
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, PR China.
authors.forename: X-D
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D047990:TNF Receptor-Associated Factor 1; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse