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 effect s of TNF through a mechanism that is not understood. Because the nuclear tr anscription factors NF-kappaB and AP-1 have recently been reported to media te anti-apoptosis and cell survival, we hypothesized that IFN-alpha potenti ates 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 an d AP-1 in a time- and dose-dependent manner as determined by EMSA. IFN-alph a blocked TNF-induced phosphorylation and degradation of the inhibitor subu nit of NF-kappaB, and suppressed NF-kappaB and AP-1 activation induced by v arious other inflammatory stimuli. NF-kappaB-dependent reporter gene expres sion activated by TNF, TNFR1, TNF receptor-associated factor 2, and IVF-kap paB-inducing kinase was also abrogated by IFN-alpha pretreatment. The suppr ession of IVF-kappaB and AP-1 correlated with the potentiation of TNF-induc ed cytotoxicity and caspase activation. Overall our results suggest that IF N-alpha potentiates the apoptotic effects of TNF possibly by suppressing NF -kappaB and AP-1 activation.