Schmidt K N, Amstad P, Cerutti P, Baeuerle P A
Institute of Biochemistry, University of Frieburg, Germany.
Chem Biol. 1995 Jan;2(1):13-22. doi: 10.1016/1074-5521(95)90076-4.
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.
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.
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.
可诱导的高等真核转录因子NF-κB可被多种刺激激活。多项证据表明，活性氧中间体（ROIs）即便不是所有这些刺激的信使，也是大部分刺激的信使。为了确定相关的ROI种类，并获得ROIs作为信使参与其中的更直接证据，我们研究了控制细胞内ROI水平的酶的水平变化是否会影响NF-κB的激活。
稳定过表达H2O2降解酶过氧化氢酶的细胞系在响应肿瘤坏死因子α（TNF）或冈田酸时激活NF-κB存在缺陷。过氧化氢酶抑制剂氨基三唑可恢复NF-κB的诱导。相反，细胞质中依赖铜/锌的超氧化物歧化酶（SOD）的稳定过表达增强了超氧化物生成H2O2的能力，增强了NF-κB的激活。细胞质中NF-κB-IκB复合物的水平未发生变化，表明NF-κB的合成未受影响。
我们的数据表明，一种ROI种类H2O2在TNF和冈田酸诱导的NF-κB翻译后激活中充当信使。超氧化物仅作为H2O2的来源间接参与其中。这些数据解释了许多抗氧化化合物对NF-κB及其靶基因激活的抑制作用。响应各种刺激时会过量产生H2O2，正常水平的过氧化氢酶似乎不足以将其完全清除。因此，H2O2可以积累并在对病原体的应答中充当细胞内信使分子。
