IRF-1 is an essential mediator in IFN-gamma-induced cell cycle arrest and apoptosis of primary cultured hepatocytes.
IFN-gamma induces cell cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, it is not yet understood what molecules regulate the mechanism. We report here that interferon regulatory factor 1 (IRF-1) is an essential molecule in these phenomena. Hepatocytes from IRF-1-deficient mice were completely resistant to IFN-gamma in apoptosis indicated by three different hallmarks such as LDH release, DNA fragmentation and the activation of caspase-3 family. Caspase-1 expression was little detected in hepatocytes, and constitutive and IFN-gamma-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-gamma-inducible caspase, caspase-11, did not change either. Thus, it is unlikely that these molecules directly regulate the mechanisms. Interestingly, IRF-1-deficient hepatocytes were also resistant to IFN-gamma-induced cell cycle arrest despite IFN-gamma-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-gamma-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-gamma did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-gamma signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis.
Kano
A
A
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuda, Midori-ku, Yokohama, 226-0026, Japan.
Haruyama
T
T
Akaike
T
T
Watanabe
Y
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053471:Caspases, Initiator; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D005260:Female; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009842:Oligopeptides / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D019014:fas Receptor / Q000235:genetics
D003374:Coumarins; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010750:Phosphoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; D019014:fas Receptor; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator