IFN-alpha suppresses activation of nuclear transcription factors NF-kappa B and activator protein 1 and potentiates TNF-induced apoptosis.
We and others have reported that IFN-alpha potentiates the apoptotic effects of TNF through a mechanism that is not understood. Because the nuclear transcription factors NF-kappaB and AP-1 have recently been reported to mediate anti-apoptosis and cell survival, we hypothesized that IFN-alpha potentiates the cytotoxic effects of TNF by suppressing TNF-induced activation of NF-kappaB and AP-1. We tested this hypothesis by pretreating human Jurkat T cells with IFN-alpha, which blocked TNF-induced activation of NF-kappaB and AP-1 in a time- and dose-dependent manner as determined by EMSA. IFN-alpha blocked TNF-induced phosphorylation and degradation of the inhibitor subunit of NF-kappaB, and suppressed NF-kappaB and AP-1 activation induced by various other inflammatory stimuli. NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TNF receptor-associated factor 2, and NF-kappaB-inducing kinase was also abrogated by IFN-alpha pretreatment. The suppression of NF-kappaB and AP-1 correlated with the potentiation of TNF-induced cytotoxicity and caspase activation. Overall our results suggest that IFN-alpha potentiates the apoptotic effects of TNF possibly by suppressing NF-kappaB and AP-1 activation.
Manna
S K
SK
Cytokine Research Laboratory, Department of Bioimmunotherapy, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Mukhopadhyay
A
A
Aggarwal
B B
BB
D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016898:Interferon-alpha / Q000502:physiology*; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051996:Transcription Factor RelA; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D002518:Ceramides; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D020169:Caspases