Oxidative stress and nuclear factor-κB activation: A reassessment of the evidence in the light of recent discoveries

doi:10.1016/S0006-2952(99)00296-8

Biochemical Pharmacology

Volume 59, Issue 1, 1 January 2000, Pages 13-23

Presented at Oxford, 10–12 June 1999.

https://doi.org/10.1016/S0006-2952(99)00296-8 Get rights and content

Abstract

Nuclear factor-κB (NFκB) is a transcription factor with a pivotal role in inducing genes involved in physiological processes as well as in the response to injury and infection. A model has been proposed whereby the diverse agents that activate NFκB do so by increasing oxidative stress within the cell. Activation of NFκB involves the phosphorylation and subsequent degradation of an inhibitory protein, IκB, and recently many of the proximal kinases and adaptor molecules involved in this process have been elucidated. Additionally, we now understand in detail the NFκB activation pathway from cell membrane to nucleus for interleukin-1 (IL-1) and tumour necrosis factor (TNF). This review revisits the evidence for the oxidative stress model in light of these recent findings, and finds little in the new information to rationalise or justify a central role for oxidative stress in NFκB activation. We demonstrate that much of the evidence for the involvement of oxidative stress is either specific to a stimulus in a particular cell line or open to reinterpretation. In particular, the activation of NFκB by hydrogen peroxide is cell-specific and distinct from physiological activators such as IL-1 and TNF, while inhibition by antioxidants, also found to be cell- and stimulus-specific, can involve diverse and unexpected targets which may be distinct from redox modulation. We conclude that in most cases the role of oxidative stress in NFκB activation is at best facilitatory rather than causal, if a role exists at all. In addition, other evidence suggests a role for lipid peroxides in pathways where such a role exists. In future, when a role for oxidative stress in a pathway is postulated, the challenge will be to show which particular kinases or adaptor molecules, if any, are redox-modulated.

Section snippets

Pathways to NFκB activation delineated

Recently, there have been a flurry of papers describing and characterising two IκB kinases, termed IKKα and IKKβ (reviewed in [10]). IKKα and β have been shown to be activated by important inducers of NFκB such as IL-1 and TNF, to specifically phosphorylate S32 and S36 of IκBα, and to be crucial for NFκB activation by these cytokines 11, 12, 13, 14, 15. The IKKs are part of a larger multiprotein complex called the IKK signalsome, which contains IKAP (IKK complex-associated protein) and NEMO

The oxidative stress model of NFκB activation

An early question in the field of NFκB research concerned the mechanism by which such a diversity of agents might activate NFκB, given that the requirements for activation were clear early on (i.e. the specific phosphorylation of an IκB). A model was proposed whereby diverse agents all activated NFκB by causing oxidative stress [30]. Oxidative stress is defined as an increase in intracellular ROS such as H₂O₂, superoxide (O₂⁻), or hydroxyl radical ( · OH). This hypothesis was based on four main

The oxidative stress model in light of recent findings

Although many of the upstream and proximal kinases important in NFκB activation have recently been identified, there has been a notable silence as to how the oxidative stress model of NFκB activation can be reconciled with the new data. Recent publications on important pathways to NFκB, such as LPS in monocytes [39] and CD28 in T cells [40], now focus on the role of the IKKs, with no mention of oxidative stress, where previously ROS were discussed as central to these pathways 35, 41, 42. In

Early work implicating a role for oxidised thiols in NFκB activation

Redox modulation of NFκB activity was first suggested by the Herzenberg group, based on the fact that the NFκB-dependent stimulation of HIV transcription by TNF or PMA was inhibited by NAC, a free radical scavenger and glutathione precursor [44]. They went on to show that in 293 cells, TNF or PMA decreased intracellular thiols and activated HIV long terminal repeat transcription, and that this was inhibited by NAC, which increased thiol levels, or potentiated by diamide, which reduced

Activation of NFκB by H₂O₂

Schreck et al. went a step further and were the first to propose that ROS were actually common second messengers in diverse pathways to NFκB [31]. They based their hypothesis on the fact that direct addition of H₂O₂, itself a source of ROS, to a subclone of Jurkat T cells could activate NFκB. This was prevented by NAC, proposed here to be acting as a free radical scavenger. NAC also blocked the activation of NFκB by cycloheximide, double-stranded RNA, calcium ionophore, TNF, PMA, IL-1, LPS, and

Production of ROS by NFκB activators

In order for the oxidative stress model of NFκB activation to be valid, stimulants of NFκB must be shown to increase intracellular ROS. This has been achieved in some cases: IL-1 and TNF have been shown to increase ROS in primary human fibroblasts [74], while LPS led to an increase in H₂O₂ production in B-cell lines [30]. H₂O₂ has also been shown to be released in response to agents that activate NFκB in other specific systems 34, 35. In another study, exhaustive tests failed to show any

Inhibition of NFκB activation by antioxidants

One of the most compelling lines of evidence for a role for oxidative stress has been the use of antioxidants to inhibit NFκB activation in response to diverse stimuli. Two compounds in particular have been extensively used, NAC and PDTC. Other antioxidants such as vitamin E derivatives [77] and α-lipoic acid [78] have also been used, and shown to inhibit NFκB activation in some cell types. As stated above, NAC is an antioxidant that can increase intracellular levels of glutathione and can also

The effect of redox-modulating enzymes on NFκB

A further line of evidence for a role for oxidative stress in NFκB activation has been the effect on NFκB of overexpressing or inhibiting enzymes that modulate the redox state of the cell. In 1992, Schreck et al. showed that overexpression of the O₂⁻-consuming enzyme SOD in MCF-7 cells potentiated TNF-mediated NFκB activation [33]. This led to H₂O₂ itself being implicated as the important oxidative second messenger, since SOD gives rise to it. However, recently contradictory results were found

Conclusions

Concerning NFκB and oxidative stress we would therefore conclude the following:

1.
Many of the important effects, such as activation by H₂O₂ or inhibition by antioxidants, have multiple and complex explanations that are often cell- or stimulus-specific. Hence, these effects do not necessarily point to a central ROS-requiring step in the process. Rather, we would suggest that a central role for H₂O₂ or ROS in a pathway to NFκB is the exception rather than the rule.
2.
We hypothesise that many

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^∗: Bowie A and O’Neill LAJ, unpublished results.

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BCP Symposium PresentationsOxidative stress and nuclear factor-κB activation∗: A reassessment of the evidence in the light of recent discoveries

Abstract

Section snippets

Pathways to NFκB activation delineated

The oxidative stress model of NFκB activation

The oxidative stress model in light of recent findings

Early work implicating a role for oxidised thiols in NFκB activation

Activation of NFκB by H2O2

Production of ROS by NFκB activators

Inhibition of NFκB activation by antioxidants

The effect of redox-modulating enzymes on NFκB

Conclusions

Cell

Trends Neurosci

Semin Cancer Biol

Cell

Cell

Cell

Cell

Cell

J Biol Chem

J Biol Chem

Chem Biol

J Biol Chem

J Biol Chem

J Biol Chem

Curr Biol

Methods Enzymol

Biochim Biophys Acta

J Biol Chem

Blood

J Biol Chem

J Biol Chem

FEBS Lett

J Biol Chem

Cell

Biochem Biophys Res Commun

Free Radic Biol Med

Cell

Arch Biochem Biophys

Biochem Biophys Res Commun

Free Radic Biol Med

Lancet

Med Hypotheses

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Pharmacol

Biochem Biophys Res Commun

FEBS Lett

Regulation of immune responses by NF-kappa B/Rel transcription factors

J Exp Med

Function and activation of NF-kappa B in the immune system

Annu Rev Immunol

A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B

EMBO J

Cigarette smoke condensate-induced adhesion molecule expression and transendothelial migration of monocytes

Am J Physiol

Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells

Proc Natl Acad Sci U S A

Identification of the receptor component of the IkappaBalpha-ubiquitin ligase

Nature

IKK-1 and IKK-2Cytokine-activated IkappaB kinases essential for NF-kappaB activation

Science

IkappaB kinase-betaNF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK

Science

A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB

Nature

IKAP is a scaffold protein of the IkappaB kinase complex

Nature

BCP Symposium Presentations
Oxidative stress and nuclear factor-κB activation∗: A reassessment of the evidence in the light of recent discoveries

Activation of NFκB by H₂O₂