Interferon-gamma induces Ice gene expression and enhances cellular susceptibility to apoptosis in the U937 leukemia cell line.
The roles of interferons (IFNs) in apoptosis are not fully understood. In this study we show that in the U937 monoblastic leukemia cell line, pretreatment with IFN-gamma enhanced sensitivity to apoptosis triggered by gamma-irradiation or antitumor agents (etoposide or adriamycin), as well as by anti-Fas antibody. In addition, IFN-gamma caused an increased expression of the interleukin-1 beta-converting enzyme (Ice) gene, following strong induction of the interferon regulatory factor-1 (IRF-1) gene, the product of which is a transcriptional activator of the Ice gene. An inhibitor of ICE/Ced-3 family proteases, Z-Asp-CH2-DCB, blocked apoptosis in control cells as well as in IFN-gamma-pretreated cells. These results suggest that enhanced susceptibility of IFN-gamma-pretreated cells to apoptosis is mediated through the induction of Ice by IRF-1. This pathway is not affected by interleukin-1 beta (IL-1 beta) since neutralizing antibody against IL-1 beta failed to suppress the IFN-gamma-mediated enhancement of cell death, and IL-1 beta itself did not mimic the effect of IFN-gamma.
Tamura
T
T
First Department of Internal Medicine, Yokohama City University School of Medicine, Japan.
Ueda
S
S
Yoshida
M
M
Matsuzaki
M
M
Mohri
H
H
Okubo
T
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D020170:Caspase 1; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology; D004790:Enzyme Induction; D005047:Etoposide / Q000494:pharmacology; D005720:Gamma Rays; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D010750:Phosphoproteins / Q000096:biosynthesis; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D019014:fas Receptor; D005047:Etoposide; D004317:Doxorubicin; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D020170:Caspase 1