Effects of oxidants and antioxidants on nuclear factor ϰB activation in three different cell lines: evidence against a universal hypothesis involving oxygen radicals

Brennan, Paul; O’Neill, Luke A.J.

doi:10.1016/0167-4781(94)00186-7

Cited by 192 publications

(120 citation statements)

References 36 publications

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“…Moreover, we found that although vitamin C was redox active in ECV304s, being capable of suppressing lipid peroxidation, the antioxidant properties of vitamin C were unlikely to be critical to its inhibitory effect, because it inhibited redoxinsensitive pathways to NF-B, and because other antioxidants failed to mimic or potentiate vitamin C inhibition. This has important implications for the purported role of oxidative stress in NF-B activation (46,47), and in fact we and others find no compelling evidence for a central role for oxidative stress in diverse pathways to NF-B (48,49), and we have consistently found many pathways to NF-B to be insensitive to antioxidants (29,44,45). Additionally, where we do see an inhibitory effect with an antioxidant on a pathway to NF-B, often multiple or unexpected targets are involved, including direct chemical modification of the NF-B complex itself (29,34,50).…”

Section: Discussionmentioning

confidence: 70%

“…The stimulus-independent inhibition by vitamin C is in contrast to the more stimulus-specific effects of the commonly used antioxidant pyrrolidine dithiocarbamate (29), and the general lack of effect of N-acetyl-L-cysteine on most of the pathways tested in this study (29,44,45). Moreover, we found that although vitamin C was redox active in ECV304s, being capable of suppressing lipid peroxidation, the antioxidant properties of vitamin C were unlikely to be critical to its inhibitory effect, because it inhibited redoxinsensitive pathways to NF-B, and because other antioxidants failed to mimic or potentiate vitamin C inhibition.…”

Section: Discussionmentioning

confidence: 77%

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Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Bowie

O’Neill

2000

The Journal of Immunology

294

173

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The transcription factor NF-κB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-κB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-κB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-κB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-κB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-κBα (inhibitory protein that dissociates from NF-κB), due to inhibition of I-κB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-κBα phosphorylation, and NF-κB activation. The results identify p38 as an intracellular target for high dose vitamin C.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 77%

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Bowie

O’Neill

2000

The Journal of Immunology

294

173

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“…For instance, NF-kB activation can be induced by treatment with H 2 O 2 in certain cell lines. However, the contribution of redox regulation in NF-kB activation is a topic for intense debate (Brennan and O'Neill, 1995;Korn et al, 2001). In addition, several research groups have reported that H 2 O 2 -induced NF-kB activation is highly cell type dependent (Anderson et al, 1994;Bowie et al, 1997;Li and Karin, 1999).…”

Section: Discussionmentioning

confidence: 99%

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

2010

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BACKGROUND: In human pancreatic adenocarcinoma, nuclear factor-kappa-B (NF-kB) transcription factor is constitutively activated that contributes to the resistance of the tumour cells to induced apoptosis. In our earlier studies, we have shown that brucein D (BD) mediated apoptosis through activation of the p38-mitogen-activated protein kinase (MAPK) signalling pathway in pancreatic cancer cells. This study investigated the function of reactive oxygen species (ROS) in BD-mediated p38-MAPK and NF-kB signalling pathways in PANC-1 cells. METHODS: Glutathione and dihydroethidium assays were used to measure the antioxidant and superoxide levels, respectively. The protein expression of p22 phox , p67 phox and p38-MAPK were examined by western blot. The NF-kB activity was evaluated by electrophoretic mobility shift assay. RESULTS: Treatment with BD depleted the intracellular glutathione levels in PANC-1 cells. Brucein D triggered the activation of NADPH oxidase isoforms, p22 phox and p67 phox while enhancing the generation of superoxide. Increases in both intracellular ROS and NADPH oxidase activity were inhibited by an antioxidant, N-acetylcysteine (NAC). Brucein D-mediated activation of p38-MAPK was also inhibited by NAC. However, inhibition of NF-kB activity in BD-treated cells was independent of ROS. In vivo studies showed that BD treatment effectively reduced the rate of xenograft human pancreatic tumour in nude mice with no significant toxicity. CONCLUSION: These data suggest that BD is an apoptogenic agent for pancreatic cancer cells through activation of the redox-sensitive p38-MAPK pathway and inhibition of NF-kB anti-apoptotic activity in pancreatic cancer cells.

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“…Reactive oxygen species have previously been implicated in the mechanism of NF B activation in response to cytokines, phorbol esters, and bacterial toxins (17,18). Conclusions have been drawn from studies using modulators of signaling events with antioxidant and metal chelating properties (18,19,21), and the overexpression of enzymes such as catalase and superoxide dismutase (20). To investigate the mechanism of NF B activation by daunorubicin, compounds were employed which included PDTC which has both antioxidant and metal chelating properties, and previously has been shown to inhibit the activation of NF B mediated by H 2 O 2 (19).…”

Section: Discussionmentioning

confidence: 99%

Daunorubicin Activates NFκB and Induces κB-dependent Gene Expression in HL-60 Promyelocytic and Jurkat T Lymphoma Cells

Boland

Foster

O’Neill

1997

Journal of Biological Chemistry

114

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The anthracycline antibiotic, daunorubicin, can induce programmed cell death (apoptosis) in cells. Recent work suggests that this event is mediated by ceramide via enhanced ceramide synthase activity. Since the generation of ceramide has been directly linked with the activation of the transcription factor, NF B, this was investigated as a novel target for the action of daunorubicin. Here we describe how treatment of HL-60 promyelocytes and Jurkat T lymphoma cells with daunorubicin results in the activation of the transcription factor NF B. The effect of daunorubicin was evident following 1-2 h treatment, which was in contrast to the time course of activation obtained with the cytokine, tumor necrosis factor, where NF B activation was detected within minutes of cellular stimulation. Activated complexes were shown to contain predominantly p50 and p65/RelA subunit components. Daunorubicin also induced I B degradation and increased the expression of an NF B-linked reporter gene. In addition, the drug was found to strongly potentiate the ability of tumor necrosis factor to induce an NF B-linked reporter gene, suggesting a synergy between these two agents in this response. These events were sensitive to the iron chelator, deferoxamine mesylate (desferal), and the anti-oxidant and metal chelator pyrrolidine dithiocarbamate. A structurally related compound, mitoxantrone, which, unlike daunorubicin, is unable to undergo redox cycling in cells, also activated NF B in a pyrrolidine dithiocarbamate-sensitive manner. A specific inhibitor of ceramide synthase, fumonisin B1, had no effect on daunorubicin induced NF B activation at a range of concentrations previously reported to block apoptosis induced by this drug. However, this agent could inhibit increases in ceramide induced by daunorubicin, in addition to blocking ceramide synthase activity from HL-60 cells which was activated in response to daunorubicin treatment. These data therefore suggest that the effect of daunorubicin on NF B is unlikely to involve ceramide, but may involve reactive oxygen species generated as a result of endogenous cellular processes rather than reductive metabolism of the drug. As NF B may be involved in apoptosis, this effect may be an important aspect of the cellular responses to this agent.

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Effects of oxidants and antioxidants on nuclear factor ϰB activation in three different cell lines: evidence against a universal hypothesis involving oxygen radicals

Cited by 192 publications

References 36 publications

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Vitamin C Inhibits NF-κB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

Daunorubicin Activates NFκB and Induces κB-dependent Gene Expression in HL-60 Promyelocytic and Jurkat T Lymphoma Cells

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