Adenoviral gene transfer of ABIN-1 protects mice from TNF/galactosamine-induced acute liver failure and lethality.
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-kappaB is believed to mediate at least part of the proinflammatory effects of TNF, and is therefore a favorite drug target. However, NF-kappaB also suppresses TNF-mediated hepatocyte apoptosis, implicating a potential cytotoxic effect of NF-kappaB inhibitors in the liver. This dual function of NF-kappaB emphasizes the need for therapeutics that can inhibit both TNF-induced NF-kappaB activation and cell death. Here we describe that adenoviral expression of the NF-kappaB inhibitory protein ABIN-1, but not an IkappaBalpha superrepressor (IkappaBalpha(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 IkappaBalpha(s) suggest a role for an NF-kappaB independent function of ABIN-1. Indeed, ABIN-1 was found to prevent not only NF-kappaB 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-kappaB inhibitory and anti-apoptotic activity in the liver, which might be of considerable interest for the treatment of inflammatory liver diseases.
Wullaert
Andy
A
Unit of Molecular Signal Transduction in Inflammation, Department of Molecular Biomedical Research, Ghent University-VIB, Technologiepark 927, B-9052 Gent, Belgium.
Wielockx
Ben
B
Van Huffel
Sofie
S
Bogaert
Veerle
V
De Geest
Bart
B
Papeleu
Peggy
P
Schotte
Peter
P
El Bakkouri
Karim
K
Heyninck
Karen
K
Libert
Claude
C
Beyaert
Rudi
R
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D022781:Hepatocytes / Q000473:pathology; D017114:Liver Failure, Acute / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D004268:DNA-Binding Proteins; D016328:NF-kappa B; C117046:TNIP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine