Role of Hydrogen Peroxide in NF-κB Activation: From Inducer to Modulator

Abstract

Hydrogen peroxide (H2O2) has been implicated in the regulation of the transcription factor NF-kappaB, a key regulator of the inflammatory process and adaptive immunity. However, no consensus exists regarding the regulatory role played by H2O2. We discuss how the experimental methodologies used to expose cells to H2O2 produce inconsistent results that are difficult to compare, and how the steady-state titration with H2O2 emerges as an adequate tool to overcome these problems. The redox targets of H2O2 in the NF-kappaB pathway--from the membrane to the post-translational modifications in both NF-kappaB and histones in the nucleus--are described. We also review how H2O2 acts as a specific regulator at the level of the single gene, and briefly discuss the implications of this regulation for human health in the context of kappaB polymorphisms. In conclusion, after near 30 years of research, H2O2 emerges not as an inducer of NF-kappaB, but as an agent able to modulate the activation of the NF-kappaB pathway by other agents. This modulation is generic at the level of the whole pathway but specific at the level of the single gene. Therefore, H2O2 is a fine-tuning regulator of NF-kappaB-dependent processes, as exemplified by its dual regulation of inflammation.

Nuclear Factor-κB (NF-κB) Inhibitory Protein IκBβ Determines Apoptotic Cell Death following Exposure to Oxidative Stress

“…To corroborate these findings, MEFs were exposed to glucose oxidase as an exogenous source of oxidative stress (22). Similar to the pattern of survival following serum starvation, WT MEFs demonstrated a time-and dose-dependent increase in cell death after glucose oxidase exposure (Fig.…”

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

“…They have in common that they are not receptor kinases by themselves, but work through associated kinases, as, for example, described for recruitment of the IL-1R-associated kinase (IRAK) in IL-1 signaling (312). In some cell types the genuine system receptors may be by-passed by H 2 O 2 (358).…”

“…Conflicting observations were also made with H 2 O 2 itself. A critical review analyzing 40 articles on NF-jB activation by H 2 O 2 alone or in conjunction with suitable cytokines revealed that H 2 O 2 did not consistently lead to NF-jB activation: an activation of NFjB was observed just in one third of the investigations, whereas in one-third H 2 O 2 inhibited NF-jB activation and had no effect whatsoever in another third (358). This puzzling scenario is hard to explain.…”

“…Revealingly, bolus administrations of 1 mM and beyond tended to inhibit NF-jB activation, and the authors recommended more physiological approaches in analyzing the problem (84, 358). The most decisive aspect of the role of H 2 O 2 , however, appeared to be the cellular system and the prevailing NF-jB-activating pathway (358). A regulatory function of H 2 O 2 or similar oxidants in NF-jB activation has, nevertheless, to be inferred from experiments with genetically modified organisms and cells overproducing or being deficient in peroxidases.…”

“…Tissue cultures, if not adequately supplemented, tend to be deficient in selenium and, thus, in GPxs (278) and Trx reductases (308). Being thereby deprived of both GSH-and Trx-dependent peroxidase systems, protein oxidations may occur upon H 2 O 2 challenge that are physiologically irrelevant, but even wellsupplemented culture cells, when suspended a medium up to 10 mM H 2 O 2 (358), may be anticipated to have their reductive capacities (GSH and Trx pools) exhausted within minutes, allowing the excess H 2 O 2 to attack protein thiols that physiologically would never be affected. In short, whereas the chemical principles of redox regulation by protein thiol modifications have quite convincingly been worked out, the physiological relevance of individual proposals may often be questioned, because of missing kinetic data and testing conditions that favor the generation of artefacts.…”