BCP Symposium PresentationsOxidative stress and nuclear factor-κB activation∗: A reassessment of the evidence in the light of recent discoveries
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
References (97)
- et al.
NF-kappa BTen years after
Cell
(1996) - et al.
NF-kappa BA crucial transcription factor for glial and neuronal cell function
Trends Neurosci
(1997) - et al.
I kappa B proteinsStructure, function and regulation
Semin Cancer Biol
(1997) - et al.
NF-kappaB activationThe I kappaB kinase revealed?
Cell
(1997) - et al.
Identification and characterization of an IkappaB kinase
Cell
(1997) - et al.
The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation
Cell
(1997) - et al.
Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation
Cell
(1998) - et al.
Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway
Cell
(1997) - et al.
Functional interactions of transforming growth factor beta-activated kinase 1 with IkappaB kinases to stimulate NF-kappaB activation
J Biol Chem
(1999) - et al.
Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-κB through IκB kinase-α and IκB kinase-β
J Biol Chem
(1999)
The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-kappa B
Chem Biol
Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1
J Biol Chem
Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells
J Biol Chem
IkappaB kinases serve as a target of CD28 signaling
J Biol Chem
Pro-inflammatory signalinglast pieces in the NF-kappaB puzzle?
Curr Biol
Assessing oxygen radicals as mediators in activation of inducible eukaryotic transcription factor NF-kappa B
Methods Enzymol
Effects of oxidants and antioxidants on nuclear factor kappa B activation in three different cell linesEvidence against a universal hypothesis involving oxygen radicals
Biochim Biophys Acta
Lipid peroxidation is involved in the activation of NF-kappaB by tumor necrosis factor but not interleukin-1 in the human endothelial cell line ECV304. Lack of involvement of H2O2 in NF-kappaB activation by either cytokine in both primary and transformed endothelial cells
J Biol Chem
Reactive oxygen intermediates activate NF-kappa B in a tyrosine kinase-dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes
Blood
Transcription factor NF-kappa B is activated by photosensitization generating oxidative DNA damage
J Biol Chem
Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury
J Biol Chem
Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation
FEBS Lett
Daunorubicin activates NFkappaB and induces kappaB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells
J Biol Chem
Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha
Cell
Interleukin-1 beta and reactive oxygen species mediate activation of c-Jun NH2-terminal kinases, in human epithelial cells, by two independent pathways
Biochem Biophys Res Commun
Redox regulation of NF-kappa B activation
Free Radic Biol Med
Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity
Cell
Responses of vascular endothelial oxidant metabolism to lipopolysaccharide and tumor necrosis factor-alpha
Arch Biochem Biophys
Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells
Biochem Biophys Res Commun
The antioxidant action of N-acetylcysteineIts reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid
Free Radic Biol Med
Inhibition of HIV progression by dithiocarb. German DTC Study Group
Lancet
Optimal dithiocarbamate structure for immunomodulator action
Med Hypotheses
Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper
J Biol Chem
The mutant plasmacytoma cell line S107 allows the identification of distinct pathways leading to NF-kappaB activation
J Biol Chem
Studies into the effect of the tyrosine kinase inhibitor herbimycin A on NF-kappa B activation in T lymphocytes. Evidence for covalent modification of the p50 subunit
J Biol Chem
Inhibition of nuclear factor kappaB by direct modification in whole cells—Mechanism of action of nordihydroguaiaritic acid, curcumin and thiol modifiers
Biochem Pharmacol
Transient overexpression of catalase does not inhibit TNF- or PMA-induced NF-kappa B activation
Biochem Biophys Res Commun
Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity
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
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Bowie A and O’Neill LAJ, unpublished results.