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A20 protects mice from D‐galactosamine/lipopolysaccharide acute toxic lethal hepatitis
Author(s) -
Arvelo Maria B.,
Cooper Jeffrey T.,
Longo Christopher,
Daniel Soizic,
Grey Shane T.,
Mahiou Jerome,
Czismadia Eva,
AbuJawdeh Graziella,
Ferran Christiane
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.31309
Subject(s) - tumor necrosis factor alpha , apoptosis , galactosamine , fulminant hepatitis , fulminant hepatic failure , lipopolysaccharide , downregulation and upregulation , fulminant , immunology , proliferating cell nuclear antigen , inflammation , medicine , necrosis , hepatitis , cancer research , biology , liver transplantation , immunohistochemistry , transplantation , gene , biochemistry , glucosamine
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‐κB. 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.