Hepatocytes can induce death of contacted cells via perforin-dependent mechanism.
The liver displays unique immunological properties including the ability to remove aberrant cells and pathogens and to induce peripheral immunotolerance. We have previously demonstrated that hepatocytes can cause cell death by a CD95 ligand-mediated mechanism. Here, we provide evidence that hepatocytes can kill other cells via a perforin-dependent pathway. Using cultured woodchuck hepatocytes and human liver cells as well as freshly isolated woodchuck, mouse, and human hepatocytes, we show that hepatocyte-mediated death of CD95-deficient target cells requires microtubule polymerization, a feature of the granule exocytosis-mediated cytotoxicity. Neutralizing anti-perforin antibodies and short-hairpin RNA directed against perforin messenger RNA confirmed the involvement of perforin in hepatocyte-mediated cell killing.


CONCLUSIONS
This study shows that hepatocytes express biologically competent perforin capable of killing susceptible cells and emphasizes the role of hepatocytes as cytotoxic effectors. This also is the first demonstration of perforin in a non-lymphoid cell type.
Guy
Clifford S
CS
Molecular Virology and Hepatology Research, Division of Biomedical Sciences, Memorial University, St. John's, Newfoundland, Canada.
Rankin
Sherri L
SL
Wang
Jinguo
J
Michalak
Tomasz I
TI
D000818:Animals; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D053804:Granzymes / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008113:Liver Neoplasms; D008392:Marmota; D051379:Mice; D008813:Mice, Inbred ICR; D054353:Perforin / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes