Suppression of steady-state, but not stimulus-induced NF-κB activity inhibits alphavirus-induced apoptosis

Recent studies have established cell type-specific, proapoptotic, or antiapoptotic functions for the transcription factor NF-kappa B. In each of these studies, inhibitors of NF-kappa B activity have been present before the apoptotic stimulus, and so the role of stimulus-induced NF-kappa B activation in enhancing or inhibiting survival could not be directly assessed. Sindbis virus, an alphavirus, induces NF-kappa B activation and apoptosis in cultured cell lines. To address whether Sindbis virus-induced NF-kappa B activation is required for apoptosis, we used a chimeric Sindbis virus that expresses a superrepressor of NF-kappa B activity. Complete suppression of virus-induced NF-kappa B activity neither prevents nor potentiates Sindbis virus-induced apoptosis, In contrast, inhibition of NF-kappa B activity before infection inhibits Sindbis virus-induced apoptosis. Our results demonstrate that suppression of steady-state, but not stimulus-induced NF-kappa B activity, regulates expression of gene products required for Sindbis virus-induced death. Furthermore, we show that in the same cell line, NF-kappa B can be proapoptotic or antiapoptotic depending on the death stimulus. We propose that the role of NF-kappa B in regulating apoptosis is determined by the death stimulus and by the timing of modulating NF-kappa B activity relative to the death stimulus.