title: A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis.
abstract: Apoptosis of hepatocytes is a seminal feature of fulminant hepatic failure. We show that the anti-apoptotic protein A20 is upregulated in hepatocytes by pro-inflammatory stimuli and functions to protect from apoptosis and limit inflammation by inhibiting NF-kappaB. Adenoviral mediated hepatic expression of A20 in BALB/c mice yields an 85% survival rate in the D-galactosamine (D-gal)/lipolysaccharide (LPS) model of acute toxic hepatitis compared with 15% to 20 % in control mice. Expression of A20 preserves normal liver function as assessed by prothrombin time. The protective effect of A20 is independent of tumor necrosis factor (TNF) inhibition. Maintaining high circulating TNF levels may be advantageous for liver regeneration. Our data supports this hypothesis as evidenced by increased proliferating cell nuclear antigen (PCNA) expression in the livers of mice expressing A20 compared with a dominant negative mutant of the TNF receptor (TNF-R), 6 hours following D-gal/LPS administration. In conclusion, these results qualify A20 as part of a physiologic, protective response of hepatocytes to injury and a promising gene therapy candidate for clinical applications aimed at preventing and treating viral and toxic fulminant hepatic failure.
authors.affiliation: Department of Surgery and Medicine, Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Arvelo
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Cooper
authors.forename: Christopher
authors.initials: C
authors.lastname: Longo
authors.forename: Soizic
authors.initials: S
authors.lastname: Daniel
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.forename: Jerome
authors.initials: J
authors.lastname: Mahiou
authors.forename: Eva
authors.initials: E
authors.lastname: Czismadia
authors.forename: Graziella
authors.initials: G
authors.lastname: Abu-Jawdeh
authors.forename: Christiane
authors.initials: C
authors.lastname: Ferran
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy*; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000096:biosynthesis; D019610:Cytoprotection; D004268:DNA-Binding Proteins; D005688:Galactosamine / Q000633:toxicity; D015316:Genetic Therapy; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D017093:Liver Failure / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D005688:Galactosamine; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse