NF-κB Potentiates Caspase Independent Hydrogen Peroxide Induced Cell Death

BackgroundThe pro-survival activity of NF-κB in response to a variety of stimuli has been extensively characterized. Although there have been a few reports addressing the pro-cell death role of NF-κB, the precise mechanism of NF-κB's pro-cell death function still remains elusive. Methodology/Principal FindingsIn the present study, we investigated the role of NF-κB in cell death induced by chronic insult with hydrogen peroxide (H2O2). Here, we show that NF-κB promotes H2O2 induced caspase independent but PARP dependent fibroblast cell death. The pro-death activity of NF-κB is due to the DNA binding activity of RelA, which is induced through IKK- mediated IκBα degradation. NF-κB dependent pro-survival genes, Bcl-2 and XIAP, were significantly repressed, while NF-κB dependent pro-death genes, TNFα and Fas Ligand, were induced in response to H2O2. Conclusions/SignificanceWe discovered an unexpected function of NF-κB, in that it potentiates chronic H2O2 exposure induced cell death, and suggest that NF-κB mediates cell death through the repression of pro-survival genes and induction of pro-death genes. Since unremitting exposure of tissues to H2O2 and other reactive oxygen species can lead to several degenerative disorders and diseases, our results have important implications for the use of NF-κB inhibitors in therapeutic drug design.