Adaptive concentrations of hydrogen peroxide suppress cell death by blocking the activation of SAPK/JNK pathway Available to Purchase

Low levels of H₂O₂ can induce cellular resistance to subsequent higher levels of H₂O₂. By using human U937 leukemia cells, it was previously shown that such an adaptive response can be induced without increasing the cellular capacity to degrade H₂O₂, thus conferring on the cells a cross-resistance to other stimuli such as serum withdrawal and C₂-ceramide. In this study, it was found that stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) acts as a common mediator of the cell death induced by high H₂O₂ concentrations, serum withdrawal and C₂-ceramide. Although SAPK/JNK activation by H₂O₂ was mediated by two upstream mitogen-activated protein kinase (MAPK) kinases MKK4 and MKK7, only MKK7 played such a role in serum withdrawal and C₂-ceramide. Interestingly, all these lethal stimuli failed to activate SAPK/JNK and its upstream kinases in the cells that were pretreated with low adaptive concentrations of H₂O₂. By contrast, the phosphorylation levels of extracellular signal-regulated kinase and p38 MAPK were not significantly influenced by this H₂O₂ pretreatment. Inducing the SAPK/JNK-suppressing effect of H₂O₂ required a time lag, which correlated with the time lag required for the induction of the adaptive response. Overall, the results suggest that H₂O₂ adaptation confers on cells a resistance to multiple stimuli by specifically blocking their ability to activate the SAPK/JNK pathways.