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Interferon-γ InducesIceGene Expression and Enhances Cellular Susceptibility to Apoptosis in the U937 Leukemia Cell Line

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Abstract

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-γ enhanced sensitivity to apoptosis triggered by γ-irradiation or antitumor agents (etoposide or adriamycin), as well as by anti-Fas antibody. In addition, IFN-γ caused an increased expression of the interleukin-1β-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 theIcegene. An inhibitor of ICE/Ced-3 family proteases, Z-Asp-CH2-DCB, blocked apoptosis in control cells as well as in IFN-γ-pretreated cells. These results suggest that enhanced susceptibility of IFN-γ-pretreated cells to apoptosis is mediated through the induction ofIceby IRF-1. This pathway is not affected by interleukin-1β (IL-1β) since neutralizing antibody against IL-1β failed to suppress the IFN-γ-mediated enhancement of cell death, and IL-1β itself did not mimic the effect of IFN-γ.

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    Citation Excerpt :

    Foam cell apoptosis is the primary cause of cell death within an advanced atherosclerotic plaque [1,2] and IFN-γ can influence this event by regulating the expression of genes involved in apoptosis. IFN-γ has been shown to induce the expression of the pro-apoptotic genes, TNF-α receptor 1 (TNFR1), and caspase 8 in THP-1 macrophages [82] and to sensitize monocytes to Fas-mediated apoptosis by inducing the expression of IL-1β converting enzyme (ICE) [83]. IFN-γ can also prime vascular SMCs for Fas-mediated apoptosis by trafficking Fas to the cell surface in a PI3K-dependent mechanism [84].

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Abbreviations used: IFN, interferon; IRF-1, interferon regulatory factor-1; ICE, interleukin-1β-converting enzyme; IL-1β, interleukin-1β; Asp, asparatic acid; Z-Asp-CH2-DCB, benzyloxycarbonyl-Asp-CH2OC(O)-2,6,-dichlorobenzamine.

1

The first two authors contributed equally to this work.

2

To whom correspondence should be addressed. Fax: +81-45-786-3444.

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