NF-κB activation by reactive oxygen species: Fifteen years later
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 (O2−) and hydroxyl radical (OH) [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 (O2−) is rapidly metabolized into H2O2 via the following dismutation reaction: 2O2− + 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 OH 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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