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Adenoviral gene transfer of ABIN‐1 protects mice from TNF/galactosamine‐induced acute liver failure and lethality
Author(s) -
Wullaert Andy,
Wielockx Ben,
Van Huffel Sofie,
Bogaert Veerle,
De Geest Bart,
Papeleu Peggy,
Schotte Peter,
El Bakkouri Karim,
Heyninck Karen,
Libert Claude,
Beyaert Rudi
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20785
Subject(s) - tumor necrosis factor alpha , proinflammatory cytokine , apoptosis , cancer research , hepatocyte , necrosis , cytokine , medicine , immunology , inflammation , biology , biochemistry , in vitro
Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a central role in acute and chronic hepatitis B and C infection and alcoholic liver disease as well as fulminant liver failure. TNF‐induced liver failure is characterized by parenchymal cell apoptosis and inflammation leading to liver cell necrosis. The transcription factor NF‐κB is believed to mediate at least part of the proinflammatory effects of TNF, and is therefore a favorite drug target. However, NF‐κB also suppresses TNF‐mediated hepatocyte apoptosis, implicating a potential cytotoxic effect of NF‐κB inhibitors in the liver. This dual function of NF‐κB emphasizes the need for therapeutics that can inhibit both TNF‐induced NF‐κB activation and cell death. Here we describe that adenoviral expression of the NF‐κB inhibitory protein ABIN‐1, but not an IκBα superrepressor (IκBα s ), completely prevents lethality in the TNF/ D ‐(+)‐galactosamine–induced model of liver failure. Protection was associated with a significant decrease in TNF‐induced leukocyte infiltration as well as hepatocyte apoptosis. The differential effects of ABIN‐1 and IκBα s suggest a role for an NF‐κB independent function of ABIN‐1. Indeed, ABIN‐1 was found to prevent not only NF‐κB activation, but also apoptosis of cultured hepatocytes in response to TNF, explaining its protective effect against TNF‐induced liver failure. In conclusion , ABIN‐1 has a dual NF‐κB inhibitory and anti‐apoptotic activity in the liver, which might be of considerable interest for the treatment of inflammatory liver diseases. (H EPATOLOGY 2005;42:381–389.)