The dsRNA-dependent protein kinase, PKR, is a central component in antiviral defense. The biological importance of PKR is further remarked by its critical role in apoptosis induced by a variety of stresses. Here, we analyzed the implication of oxidative stress in the induction of PKR-dependent apoptosis in Jurkat cells. Our results revealed that reactive oxygen species (ROS) induced endogenous pkr gene expression at the transcriptional level by activating the interferon (IFN)-gamma gene. However, IFN-gamma siRNA expression abrogated the H2O2-mediated pkr induction. The radical scavenger N-acetyl-L-cysteine profoundly inhibited pkr induction via the reduction of IFN-gamma expression. The treatment of cells with the specific JAK-STAT inhibitor, AG490, reduced the PKR expression, and Suppressed PKR-dependent cell death. Finally, siRNA-mediated depletion of IFN-gamma or pkr efficiently downregulated H2O2-mediated apoptotic cell death. These results indicated that oxidative stress induces PKR expression essentially via the IFN-gamma activation signal, and causes apoptosis in Jurkat T cells. (C) 2008 Elsevier Inc. All rights reserved.