Hepadnaviral infection augments hepatocyte cytotoxicity mediated by both CD95 ligand and perforin pathways.
OBJECTIVE
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-gamma 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.
Guy
Clifford S
CS
Molecular Virology and Hepatology Research Group, Health Sciences Centre, Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St John's, NF, Canada.
Wang
Jinguo
J
Michalak
Tomasz I
TI
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000276:immunology*; D053804:Granzymes / Q000378:metabolism; D018347:Hepadnaviridae Infections / Q000276:immunology* / Q000473:pathology; D006508:Hepatitis Antibodies / Q000097:blood; D018963:Hepatitis Antigens / Q000097:blood; D017919:Hepatitis B Virus, Woodchuck; D022781:Hepatocytes / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008392:Marmota; D054353:Perforin / Q000276:immunology*; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology
D017252:CD3 Complex; D053222:Fas Ligand Protein; D006508:Hepatitis Antibodies; D018963:Hepatitis Antigens; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes