Elsevier

Biochemical Pharmacology

Volume 72, Issue 11, 30 November 2006, Pages 1493-1505
Biochemical Pharmacology

NF-κB activation by reactive oxygen species: Fifteen years later

https://doi.org/10.1016/j.bcp.2006.04.011Get rights and content

Abstract

The transcription factor NF-κB plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-κB may be activated by H2O2, several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to IκBα Y42 phosphorylation independently of IκB kinase (IKK), recent findings suggest that H2O2 activates NF-κB mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and 1O2) and reactive nitrogen species on NF-κB activation. Finally, we critically review the recent data highlighting the role of ROS in NF-κB activation by proinflammatory cytokines (TNF-α and IL-1β) and lipopolysaccharide (LPS), two major components of innate immunity.

Section snippets

Reactive oxygen species and cellular signalling

Molecular oxygen is an essential molecule for all aerobic life forms, notably for the cell to obtain energy as a form of ATP. Under normal or pathologic conditions, O2 is often transformed into highly reactive forms, called reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), superoxide anion (O2radical dot) and hydroxyl radical (OHradical dot) [1], [2]. ROS are generated through multiple sources in the cell, such as the electron transport chain in mitochondria, ionizing radiations [3], [4] and through

NF-κB and NF-κB-activating pathways

The transcription factor NF-κB is crucial in a series of cellular processes, such as inflammation, immunity, cell proliferation and apoptosis. It consists of homo- or heterodimers of a group of five proteins, namely NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its precursor p100), p65/RelA, c-Rel and RelB [21]. In the resting state, NF-κB is sequestered in the cytoplasm of the cell through its tight association with inhibitory proteins called IκBs, comprising IκBα, IκBβ, IκBγ, IκBɛ,

NF-κB activation by H2O2

The vast majority of studies concerning oxidant-induced NF-κB activation have used H2O2 as a direct source of ROS. After its production in the mitochondria or through specialised enzymes, superoxide anion (O2radical dot) is rapidly metabolized into H2O2 via the following dismutation reaction: 2O2radical dot + 2H+  O2 + H2O2. This reaction occurs either spontaneously or is catalysed in cells by superoxide dismutase (SOD). H2O2 is a mild oxidant mediating its effects by itself or via its transformation into OHradical dot in the

NF-κB inhibition by ROS: the case of lung epithelial cells

Very few works have highlighted an inhibitory effect of H2O2 on NF-κB activation by pro-inflammatory cytokines. Nevertheless, a simultaneous exposure to pro-inflammatory mediators and ROS is likely to occur in inflammatory states. Korn et al. reported that, in this case, H2O2 is capable of inhibiting TNF-induced NF-κB activation in lung epithelial cells by reducing IKKβ activity through oxidation of cysteine residues in the IKK complex [56]. One likely candidate is cysteine 179 in the IKKβ

Modulation of NF-κB activation by other reactive oxygen species and reactive nitrogen species

Although the vast majority of studies concerning oxidant-induced NF-κB activation have focussed on H2O2, other oxidants, like hypochlorous acid (HOCl) and singlet oxygen (1O2), have been shown to modulate NF-κB activation. On the other hand, some works have also highlighted NF-κB regulation by peroxinitrite which is a reactive nitrogen species. In this chapter, we will briefly summarize the current knowledge in that matter.

Involvement of reactive oxygen species in NF-κB activation by pro-inflammatory cytokines and LPS

To explain the fact that such a diversity of inducers activate NF-κB via the same IKK-dependent pathway, a model has emerged suggesting that all NF-κB activators cause an oxidative stress that is mainly responsible for IKK activation and IκBα degradation. This model is based on several observations, including that most of NF-κB-inducers trigger the formation of ROS [81], [82] and that several antioxidants can block NF-κB activation [83]. Indeed, an important number of papers have been published

Conclusions and perspectives

NF-κB redox regulation has been intensely studied in several cell-types and biological conditions. It is now clear that H2O2-induced NF-κB activation mechanism relies mainly on IKK activation, but the redox-sensitive pathways triggering this activation are quite different depending on the cell-type considered, which renders the drawing up of consensual models and the establishment of therapeutical strategies quite difficult to consider. The solution would be to study NF-κB redox regulation in

Acknowledgements

G.G. is a PhD student supported by the FRIA (Brussels, Belgium), S.L.-P. and J.P. are Research Associate and Research Director from the National Fund for Scientific Research (FNRS) (Brussels, Belgium). Results from our laboratory described in this paper have been obtained with the support of the FNRS, the IAP5/12 program and the ARC (contract 04/09-323).

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