IFN-alpha suppresses activation of nuclear transcription factors NF-kappa B and activator protein 1 and potentiates TNF-induced apoptosis

Abstract

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.