c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte.
Interferon-gamma (IFNgamma) is a central component of the complex cytokine and inflammatory response that contributes to liver cell injury in hepatitis. We report that in the primary hepatocyte IFNgamma synergizes with the mechanistically distinct apoptotic stimuli CD95, tumour necrosis factor-alpha (TNFalpha) and UV-irradiation. For the first time in primary hepatocytes, we show that IFNgamma-mediated apoptotic signalling requires the cell surface interaction of CD95 and its ligand, and we demonstrate that IFNgamma induces soluble CD95 ligand release from hepatocyte monolayers. Utilizing c-myc phosphorothioate antisense fragments, we suppresses hepatocyte apoptosis induced by IFNgamma. In summary, we identify apoptotic pathways that contribute to IFNgamma-mediated cell death. The hepatocellular response to IFNgamma signalling can be modulated by cytokines and by the interruption of CD95 interaction with its ligand. We present evidence to suggest that c-myc contributes to IFNgamma signalling.
McCullough
C T
CT
Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Road South, Edinburgh, UK.
Tura
B J
BJ
Harrison
D J
DJ
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013194:Staining and Labeling; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D019014:fas Receptor / Q000276:immunology
D053222:Fas Ligand Protein; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma