NF-kappa B 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 pre viously demonstrated that H2O2 can induce such an adaptive response without elevating the cellular capacity to degrade H2O2, and were able to confer t he cells a cross-resistance to an H2O2-independent lethal stimulus, C-2-cer amide. In this study, it was found that the adaptation is accompanied by th e translocation of cytoplasmic NF-kappaB to the nuclei. This event was prom oted or abolished when either IKK alpha or a dominant negative mutant of I kappaB, respectively, was overexpressed. The overexpression of IKK alpha al so resulted in the suppression of H2O2-induced cell death and DNA fragmenta tion, whereas these events were accelerated by the expression of the I kapp aB mutant. The protective effect of IKK alpha was accompanied neither by an elevation of protein levels of various antioxidant enzymes such as catalas e, superoxide dismutase, and glutathione peroxidase, nor by an increase in the cellular capacity to consume H2O2. Moreover, the overexpression of IKK alpha resulted in an enhancement of H2O2-induced resistance to C-2-ceramide . The overall data suggest that NF-kappaB mediates the H2O2 adaptation indu ced in a manner independent of H2O2-degrading activity. (C) 2001 Elsevier S cience Inc.