title: Aggravation of post-ischemic liver injury by overexpression of A20, an NF-κB suppressor.
abstract: OBJECTIVE
  A20 is an intracellular ubiquitin-editing enzyme that plays an important role in the negative feedback regulation of NF-κB activation in response to a diverse range of stimuli. Liver ischemia/reperfusion injury is associated with rapid activation of NF-κB signaling, but the role of NF-κB in hepatic ischemia/reperfusion injury remains controversial. The NF-κB signaling pathway mediates both protective and deleterious effects in the liver. Here, we examined whether A20 inhibited or aggravated hepatic ischemia/reperfusion injury.
  
  
  METHODS
  We used IκBα super-repressor as a positive control and overexpressed A20 and IκBα super-repressor in the liver of C57BL/6 mice. Mice underwent 45min of partial hepatic ischemia and were then reperfused.
  
  
  RESULTS
  Protein level of A20 was increased after reperfusion. Mice subjected to ischemia/reperfusion injury showed increased NF-κB activation, as evidenced by phosphorylation of IκBα and nuclear translocation of NF-κB. Prior transfection with Ad-A20 or Ad-IκBα super-repressor attenuated NF-κB activation and aggravated liver injury. Serum aminotransferases and proinflammatory cytokines, hepatocellular necrosis, and hepatic neutrophil infiltration were markedly increased compared to those of uninfected or control virus infected mice. In addition, A20 abolished the beneficial effect of ischemic preconditioning.
  
  
  CONCLUSIONS
  Our results suggest that inhibition of NF-κB activation by A20 aggravated partial hepatic ischemia/reperfusion injury. Understanding how the NF-κB pathway plays a role in directing a clinical outcome may lead to better prospects of more rational approaches to reduce post-ischemic liver injury.
authors.affiliation: Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Jiahua
authors.initials: J
authors.lastname: Yu
authors.forename: Hwa-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Hee-Chul
authors.initials: HC
authors.lastname: Yu
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
authors.forename: Myoung Ja
authors.initials: MJ
authors.lastname: Chung
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D020672:I-kappa B Proteins / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011994:Recombinant Proteins; D000072000:NF-KappaB Inhibitor alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse