NFκB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis

NF kappa B is an essential survival factor in several physiological conditions such as embryonal liver development and liver regeneration. However, NF kappa B is also a main mediator of the cellular response to a variety of extracellular stress stimuli, and it has been shown that some viral-induced host cell apoptosis appears to be dependent on NF kappa B activation, The activation of NF kappa B upon viral infection may be a rapid way of initiating an innate immune response against the viral particles, We have assessed the role of NFkB during the early phase of adenoviral hepatitis in a nude mouse model using an adenoviral vector expressing a mutant form of I kappa B alpha. Administration of a LacZ-expressing adenoviral vector induces NFkB DNA and correlates with the up-regulation of Fas (CD95) mRNA, but not Fast (CD95L) mRNA, during the early phase of adenoviral hepatitis. The rapid increase in NF kappa B DNA binding after adenoviral infection of the liver could be very effectively inhibited by I kappa B alpha. Compared with the LacZ control virus, the I kappa B alpha-expressing adenoviral vector inhibits the increase of Fas (CD95) mRNA expression, in particular in the very early phase of the hepatitis. Reporter gene experiments in hepatoma cell Lines with a Fas promoter-luciferase construct indicated that the repression of Fas (CD95) mRNA by I kappa B alpha was transcriptionally mediated. The functional relevance of the NF kappa B-dependent increase in Fas (CD95) transcription was assessed by caspase 3 assays and terminal dUTP nick-end labeling tests. Compared with the control, I kappa B alpha adenoviral infection resulted in reduced caspase 3 activity during the early phase of viral hepatitis and in a prevention of Liver cell apoptosis 24 h after adenoviral administration. Therefore our study demonstrates a new pro-apoptotic function of NF kappa B in Fas (CD95)-mediated apoptosis of hepatocytes. Interestingly, NF kappa B mediates liver cell apoptosis upon viral infection even in a phase where tumor necrosis factor-alpha is already induced, as shown by the time curves of tumor necrosis factor-alpha serum levels, Therefore, the pro- or anti-apoptotic role of NF kappa B appears to be more determined by the nature of the death stimulus than by the origin of the tissue.