Vanadate Facilitates Interferon α-mediated Apoptosis That Is Dependent on the Jak/Stat Pathway

Abstract

Type I interferon (IFN)-dependent inhibition of cell growth can occur either in the absence or presence of apoptosis. The mechanisms that determine whether or not cells undergo apoptosis after exposure to IFN-α are not clear. This study shows that a variety of cell lines that display growth inhibition but not apoptosis in response to IFN-α will undergo programmed cell death when low concentrations of the protein-tyrosine phosphatase inhibitor vanadate are added with IFN-α. In contrast, the combination of tumor necrosis factor-α with vanadate did not trigger apoptosis in these cells. Caspase-3 activity was detected only in cells exposed to IFN-α and vanadate but not to IFN-α or vanadate alone. The ability of IFN-α and vanadate to induce apoptosis did not require expression of p53 and was blocked by N-acetyl-L-cysteine. Activation of the Jak/Stat pathway and expression of IFN-inducible genes was not altered by incubation of cells with IFN-α and vanadate compared with IFN-α alone. However, mutant cells lacking Stat1, Stat2, Jak1, or Tyk2, or cells expressing kinase inactive Jak1 or Tyk2 did not undergo apoptosis in the presence of IFN-α and vanadate. These results suggest that IFN-α stimulation of Stat-dependent genes is necessary, but not sufficient, for this cytokine to induce apoptosis. Another signaling cascade that involves the activity of a protein-tyrosine phosphatase and/or the generation of reactive oxygen species may play an important role in promoting IFN-α-induced apoptosis.