Hepadnaviral infection augments hepatocyte cytotoxicity mediated by both CD95 ligand and perforin pathways
Article first published online: 12 NOV 2009
© 2009 John Wiley & Sons A/S
Volume 30, Issue 3, pages 396–405, March 2010
How to Cite
Guy, C. S., Wang, J. and Michalak, T. I. (2010), Hepadnaviral infection augments hepatocyte cytotoxicity mediated by both CD95 ligand and perforin pathways. Liver International, 30: 396–405. doi: 10.1111/j.1478-3231.2009.02168.x
- Issue published online: 18 JAN 2010
- Article first published online: 12 NOV 2009
- Received 4 July 2009Accepted 17 October 2009
- CD95-mediated cell killing;
- hepadnaviral infection;
- hepatic innate immunity;
- hepatocyte cytotoxicity;
- perforin-dependent cell killing
Background/Aim: Recently, we documented that hepatocytes can eliminate contacted cells via the CD95 ligand (CD95L)–CD95 pathway and that they are also equipped in perforin and granzyme B and can eradicate other cells via the granule exocytosis mechanism. The aim of this study was to assess whether hepadnaviral infection modifies hepatocyte-mediated cell killing.
Methods: Primary hepatocytes from woodchucks with progressing or resolved hepadnaviral hepatitis and hepatocyte lines transfected with woodchuck hepatitis virus (WHV) genes were examined for cytotoxic effector activity against cell targets susceptible to CD95L and/or perforin-dependent killing. Hepatocytes from healthy animals served as controls.
Results: Actively progressing and resolved hepadnaviral hepatitis is associated with a significantly greater capacity of hepatocytes to kill contacted cells. Both hepatocyte CD95L- and perforin-dependent cytotoxicity were augmented. Hepatocytes transfected with WHV X gene, but not those with complete WHV genome or virus envelope or core gene, transcribed significantly more CD95L and perforin and killed cell targets more efficiently. Exposure to interferon-γ profoundly enhanced hepatocyte cell killing.
Conclusions: Hepatocyte cytotoxic potential is significantly augmented during and following resolution of active hepadnaviral hepatitis. Hepatocyte cytotoxic activity may contribute to both liver physiological functions and the pathogenesis and progression of liver disease, including viral hepatitis.