Hepatitis B Virus Infection triggers AP–1 dependent CD95Ligand expression in HepG2 cells

An acute Hepatitis B Virus (HBV)-infection is characterized by a vigorous, polyclonal and multi-specific CD8+ T cell response. CD8+ T cells are the main effector cells responsible for viral clearance and disease pathogenesis during an acute HBV-infection. CD95 Ligand (CD95L) expression is generally restricted to a few cell types, e.g. T cells, macrophages and NK cells. We have previously shown that an intact CD95 signalling pathway is required for elimination of HBV-infected hepatocytes. Furthermore, we have identified an AP–1 element in the CD95L promoter which is essential for the transactivation of the CD95L gene. The aim of this study was to analyze CD95L transactivation and -expression in HBV-infected hepatocytes. Adenoviral transfer of HBV constructs into the hepatoma cell line HepG2 resulted in the transactivation, transcription and expression of CD95L. Four different CD95L promoter constructs (CD95L –36, –220, –536, and –1204/+100) have been used to identify the binding site responsible for CD95L transactivation in HBV-infected hepatocytes. However, there was no particular difference in the induction of the different constructs. This led to the hypothesis that no binding site between –36 and –1204 functions as the major binding site responsible for CD95L transactivation in HBV-infected hepatocytes. Instead, inhibition of JNK resulted in a significant inhibition of CD95L transactivation. Since HBV infection resulted in the phosphorylation of JNK (Jun-NH2 kinase) and the subsequent activation of the transcription factor AP–1, we postulate that CD95L transactivation is triggered by Thr183/Tyr185 phosphorylation of JNK. We characterized the molecular mechanisms resulting in CD95L expression in HBV-infected hepatocytes. In this study we provide evidence that HBV infection leads to the phosphorylation of JNK, AP–1 dependent transactivation of CD95L and finally CD95L expression, suggesting a potential CD95L activation independent of CD8+ T cells in HBV infection.

CD95L - HBV