THE ROLES OF HYDROGEN-PEROXIDE AND SUPEROXIDE AS MESSENGERS IN THE ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B

Background: The inducible, higher eukaryotic transcription factor NF-kappa B is activated by a variety of stimuli. Several lines of evidence have suggested that reactive oxygen intermediates (ROIs) serve as messengers for most if not all of these stimuli. To identify the relevant ROI species and to gain more direct evidence for an involvement of ROIs as messengers, we investigated whether changes in the levels of enzymes that control intracellular ROI levels affect the activation of NF-kappa B. Results: Cell lines stably overexpressing the H2O2-degrading enzyme catalase were deficient in activating NF-kappa B in response to tumor necrosis factor alpha (TNF) or okadaic acid. The catalase inhibitor aminotriazol restored NF-kappa B induction. In contrast, stable overexpression of cytoplasmic Cu/Zn-dependent superoxide dismutase (SOD), which enhances the production of H2O2 from superoxide, potentiated NF-kappa B activation. The level of cytoplasmic NF kappa B-I kappa B complex was unchanged, indicating that synthesis of NF-kappa B was not affected. Conclusions: Our data show that one ROI species, H2O2, acts as a messenger in the TNF- and okadaic acid-induced post-translational activation of NF-kappa B. Superoxide is only indirectly involved, as a source for H2O2. These data explain the inhibitory effects of many antioxidative compounds on the activation of NF-kappa B and its target genes. H2O2 is overproduced in response to various stimuli, and normal levels of catalase appear insufficient to remove it completely. H2O2 can therefore accumulate and act as an intracellular messenger molecule in the response to pathogens.