NF-κB mediates the adaptation of human U937 cells to hydrogen peroxide

Low doses of oxidative stress can induce cellular resistance to subsequent higher doses of the same stress. By using human U937 leukemia cells, we previously demonstrated that H2O2 can induce such an adaptive response without elevating the cellular capacity to degrade H2O2, and were able to confer the cells a cross-resistance to an H2O2-independent lethal stimulus, C2-ceramide. In this study, it was found that the adaptation is accompanied by the translocation of cytoplasmic NF-κB to the nuclei. This event was promoted or abolished when either IKKα or a dominant negative mutant of IκB, respectively, was overexpressed. The overexpression of IKKα also resulted in the suppression of H2O2-induced cell death and DNA fragmentation, whereas these events were accelerated by the expression of the IκB mutant. The protective effect of IKKα was accompanied neither by an elevation of protein levels of various antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase, nor by an increase in the cellular capacity to consume H2O2. Moreover, the overexpression of IKKα resulted in an enhancement of H2O2-induced resistance to C2-ceramide. The overall data suggest that NF-κB mediates the H2O2 adaptation induced in a manner independent of H2O2-degrading activity.