Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 16, Pages 13153-13159Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M007646200
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We investigated the molecular mechanism of the synergism between interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha) documented in a variety of biological occasions such as tumor cell death and inflammatory responses. IFN gamma /TNF alpha synergistically induced apoptosis of ME-180 cervical cancer cells. IFN gamma induced STAT1 phosphorylation and interferon regulatory factor 1 (IRF-1) expression. Transfection of phosphorylation-defective STAT1 inhibited IFN gamma /TNF alpha -induced apoptosis, whereas IRF-1 transfection induced susceptibility to TNF alpha. Dominant-negative I kappaB alpha transfection sensitized ME-180 cells to TNF alpha. IFN gamma pretreatment attenuated TNF alpha- or p65-induced NF-KB reporter activity, whereas it did not inhibit p65 translocation or DNA binding of NF-KB, IRF-1 transfection alone inhibited TNF alpha -induced NF-KB activity, which was reversed by coactivator p300 overexpression. Caspases were activated by IFN gamma /TNF alpha combination; however, caspase inhibition did not abrogate IFN gamma /TNF alpha -induced cell death. Instead, caspase inhibitors directed IFN gamma TNF alpha -treated ME-180 cells to undergo necrosis, as demonstrated by Hoechst 33258/propidium iodide staining and electron microscopy. Taken together, our results indicate that IFN gamma and TNFa synergistically act to destroy ME-180 tumor cells by either apoptosis or necrosis, depending on caspase activation, and STAT1/IRF-1 pathways initiated by IFN gamma play a critical role in IFN gamma /TNF alpha synergism by inhibiting cytoprotective NF-KB, IFN gamma /TNF alpha synergism appears to activate cell death machinery independently of caspase activation, and caspase activation seems to merely determine the mode of cell death.
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