Inhibition of NF-κB activity and cFLIP expression contribute to viral-induced apoptosis

Virus-induced activation of nuclear factor-kappa 8 (NF-kappa B) is required for Type 3 (T3) reovirus-induced apoptosis. We now show that NF-kappa B is also activated by the prototypic Type 1 reovirus strain Lang (T1L), which induces significantly less apoptosis than T3 viruses, indicating that NF-kappa B activation alone is not sufficient for apoptosis in reovirus-Infected cells. A second phase of virus-induced NF-kappa B regulation, where NF-kappa B activation is inhibited at later times following infection with T3 Abney (T3A), is absent in T1L-Infected cells. This suggests that inhibition of NF-kappa B activation at later times post infection also contributes to reovirus-induced apoptosis. Reovirus-induced inhibition of stimulus-induced activation of NF-kappa B is significantly associated with apoptosis following infection of HEK293 cells with reassortant reoviruses and is determined by the T3 S1 gene segment, which is also the primary determinant of reovirus-induced apoptosis. Inhibition of stimulus-induced activation of NF-kappa B also occurs following infection of primary cardiac myocytes with apoptotic (813) but not non-apoptotic (T1L) reoviruses. Expression levels of the NF-kappa B-regulated cellular FLICE inhibitory protein (cFLIP) reflect NF-kappa B activation in reovirus-Infected cells. Further, inhibition of NF-kappa B activity and cFLIP expression promote T1L-induced apoptosis. These results demonstrate that inhibition of stimulus-induced activation of NF-kappa B and the resulting decrease in cFLIP expression promote reovirus-induced apoptosis.