Redox Regulation of NF-kappa B Activation

Flohé, Leopold; Brigelius‐Flohé, Regina; Saliou, Claude; Traber, Maret G.; Packer, Lester

doi:10.1016/s0891-5849(96)00501-1

Cited by 807 publications

(485 citation statements)

References 113 publications

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“…This finding is in agreement with the observations of others who demonstrated a similar specificity in NFκB activation in both normal and malignant cells following exposure to thiol-containing drugs such as N-acetyl-L-cysteine, dithiothreitol, 2-mercaptoethanol, WR1065, and oltipraz [14,16,18]. This is not surprising since NFκB is a well-characterized redox-sensitive transcription factor whose activation is known to be induced by both oxidative stress [14][15][16][17][18] and reducing agents that are capable of altering the redox state of the cysteine 62 residue of its p50 subunit [35]. Correlating with NFκB activation is the robust expression of the MnSOD gene.…”

Section: Discussionsupporting

confidence: 92%

“…Amifostine, as well as NPT in general, can participate in reductive/oxidative reactions that in turn can affect redox-sensitive cellular processes involving the activation of certain transcription factors, expression of genes, and activities of proteins [14][15][16][17][18]. In particular, amifostine, NAC, and oltipraz have each been observed to be effective in activating the redox sensitive nuclear transcription factor κB (NFκB) and enhancing the expression of the antioxidant gene MnSOD [14,16,18].…”

Section: Introductionmentioning

confidence: 99%

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Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

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The free radical scavenger WR1065 (SH) is the active thiol form of the clinically approved cytoprotector amifostine. At doses of 40 μM and 4 mM it can activate the redox-sensitive nuclear transcription factor κB (NFκB) and elevate the expression of the antioxidant gene manganese superoxide dismutase (MnSOD) in human microvascular endothelial cells (HMEC). MnSOD contains binding motifs for a number of transcription factors other than NFκB and codes for a potent antioxidant enzyme localized in the mitochondria that is known to confer enhanced radiation resistance to cells. The purpose of this study was to determine the effect of WR1065 exposure on the various transcription factors known to affect MnSOD expression along with the subsequent kinetics of intracellular elevation of MnSOD protein levels and associated change in sensitivity to ionizing radiation in HMEC. Cells were grown to confluence and exposed to WR1065 for 30 min. Affects on the transcription factors AP1, AP2, CREB, NFκB, and Sp1 were monitored as a function of time ranging from 30 min to 4 h after drug exposure using a gel-shift assay. Only NFκB exhibited a marked activation and that occurred 30 min following the cessation of drug exposure. MnSOD protein levels, as determined by Western blot analysis, increased up to 16-fold over background control levels by 16 h following drug treatment, and remained at 10-fold or higher levels for an additional 32 h. MnSOD activity was evaluated using a gel-based assay and was found to be active throughout this time period. HMEC were irradiated with X-rays either in the presence of 40 μM or 4 mM WR1065 or 24 h after its removal when MnSOD levels were most elevated. No protection was observed for cells irradiated in the presence of 40 μM WR1065. In contrast, a 4 mM dose of WR1065 afforded an increase in cell survival by a factor of 2. A "delayed radioprotective" effect was, however, observed when cells were irradiated 24 h later, regardless of the concentration of WR1065 used. This effect is characterized as an increase in survival at the 2 Gy dose point, i.e., a 40% increase in survival, and an increase in the initial slope of the survival curve by a factor of 2. The anti-inflammatory sesquiterpene lactone, Helenalin, is an effective inhibitor of NFκB activation. HMEC were exposed to Helenalin for 2 h at a nontoxic concentration of 5 μM prior to exposure to WR1065. This treatment not only inhibited activation of NFκB by WR1065, but also inhibited the subsequent elevation of MnSOD and the delayed radioprotective effect. A persistent marked elevation of MnSOD in cells following their exposure to a thiol-containing reducing agent such as WR1065 can result in an elevated resistance to the cytotoxic effects of ionizing radiation and represents a novel radioprotection paradigm.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Indeed, ROS are implicated as participants in many intracellular signaling pathways, including activation of stress-and mitogen-activated protein kinases and the nuclear transcription factors c-Jun and NF-κB in other cell types (Guyton et al, 1996;Laderoute et al, 1997;Flohe et al, 1997;Lander, 1997;Hwang et al, 2004;Pearl-Yafe et al, 2004). RPE cells were less susceptible to death induced by H 2 O 2 or paraquat, and had greater CuZnSOD, catalase and GPX enzymatic activity, compared to other cell types (Jarrett et al, 2006;Lu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells

Yang

Elner

Bian

et al. 2007

Experimental Eye Research

365

242

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Reactive oxygen species (ROS) generated during inflammation are believed to play critical roles in various ocular diseases. However, the underlying mechanisms remain poorly understood. We investigated if pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interferon-γ (IFN-γ), induce ROS in human retinal pigment epithelial (RPE) cells. TNF-α, IL-1β and IFN-γ increased both intracellular and extracellular ROS production in a time-and dosedependent manner. Thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial respiratory chain, blocked TNF-α-and IFN-γ-, but not IL-1β-induced ROS, whereas other two mitochondrial respiratory chain inhibitors, rotenone and antimycin A, had no effect. NADPH oxidase inhibitor (diphenylene iodinium) abolished the ROS production induced by IL-1β or IFN-γ, but not by TNF-α, whereas 6-aminonicotinamide (6AN), an inhibitor of the hexose monophosphate shunt (HMS), had no significant effects on the ROS induced by all three cytokines. ROS scavengers, pyrrolidinedithiocarbamate (PDTC) and N-acetyl-cysteine (NAC), reduced the levels of ROS induced by TNF-α, IL-1β and IFN-γ (P < 0.05). Collectively, these results demonstrate that TNF-α, IL-1β and IFN-γ increase mitochondrial-and NADPH oxidase-generated ROS in human RPE cells.

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“…Virtually every step of the NFkB signaling cascade is comprised of redox-sensitive proteins whose activities are modulated upon changes in ROS, some of these in a negative fashion (reviewed in Flohe et al, 1997;Janssen-Heininger et al, 2000;. NFkB must be in a reduced form to exhibit DNA binding activity, thus reducing agents (dithiothreitol and mercaptoethanol) enhance DNA binding activity, while oxidizing agents (diamide) inhibit this activity.…”

Section: Nuclear Factor Kb (Nf Kb) Signalingmentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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Redox Regulation of NF-kappa B Activation

Cited by 807 publications

References 113 publications

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells

Cellular response to oxidative stress: Signaling for suicide and survival*

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