<i>N</i>‐Acetylcysteine suppresses TNF‐induced NF‐κB activation through inhibition of IκB kinases

Oka, Sarang; Kamata, Hideaki; Kamata, Keiko; Yagisawa, Hitoshi; Hirata, Hajime

doi:10.1016/s0014-5793(00)01464-2

Cited by 161 publications

(119 citation statements)

References 46 publications

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“…In these experiments antioxidants inhibited LPS-induced activation of both IKK␤ and IKK␣. A previous study using HeLa cells showed that NAC suppressed NF-B activation through inhibition of IKK, but did not examine upstream kinases (55). As expected, we found that inhibition of IKK activation by antioxidants resulted in preservation of levels of IB␣, providing a mechanism for the observed reduction in translocation of NF-B to the nucleus and suppression of the expression of NF-B-dependent cytokines under such conditions.…”

Section: Discussionsupporting

confidence: 75%

Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

Asehnoune

Strassheim

Mitra

et al. 2004

The Journal of Immunology

508

340

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Although oxidative stress has been thought to play a general role in the activation of NF-κB, the involvement of reactive oxygen species (ROS) in facilitating nuclear translocation of NF-κB in neutrophils has not been described. In addition, the mechanisms by which ROS modulate the transcriptional activity of NF-κB in response to Toll-like receptor 4 (TLR4)-dependent signaling are not well characterized. To examine these issues, oxidant-dependent signaling events downstream of TLR4 were investigated in neutrophils stimulated with LPS. Pretreatment of neutrophils with the antioxidants N-acetylcysteine or α-tocopherol prevented LPS-induced nuclear translocation of NF-κB. Antioxidant treatment of LPS-stimulated neutrophils also inhibited the production of proinflammatory cytokines (TNF-α, macrophage inflammatory protein-2, and IL-1β), as well as activation of the kinases IκB kinase α, IκB kinase β, p38, Akt, and extracellular receptor-activated kinases 1 and 2. The decrease in cytoplasmic levels of IκBα produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or α-tocopherol. Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants. These results demonstrate that proximal events in TLR4 signaling, at or antecedent to IRAK-1 and IRAK-4 activation, are oxidant dependent and indicate that ROS can modulate NF-κB-dependent transcription through their involvement in early TLR4-mediated cellular responses.

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Section: Discussionsupporting

confidence: 75%

Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

Asehnoune

Strassheim

Mitra

et al. 2004

The Journal of Immunology

508

340

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“…Because NF-nB is controlled primarily by IKK, it is conceivable that blocking IKK will result in dramatic cell death, thus improving the anticancer activity of TNFa. This notion has been strongly supported by many studies using nonselective IKK inhibitors (17)(18)(19)(20)(21)(22). Recently, Frelin and colleagues (23) showed that AS602868, a specific small molecule IKKh inhibitor, potentiated the proapoptotic effect of TNFa in Jukat leukemia cells.…”

Section: Introductionmentioning

confidence: 88%

IκBα Kinase Inhibitor IKI-1 Conferred Tumor Necrosis Factor α Sensitivity to Pancreatic Cancer Cells and a Xenograft Tumor Model

et al. 2008

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Tumor necrosis factor A (TNFA) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IKBA kinase (IKK), which in turn activates nuclear factor-KB (NF-KB) to help cancer cells survive. Therefore, inhibition of TNFAinduced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients. This study reveals IKI-1 as a potent small molecule inhibitor of IKKA and IKKB, which effectively blocked TNFA-mediated IKK activation and subsequent NF-KB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFA-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFA with IKI-1 had superior potency than either agent alone. This increased potency was due primarily to the increased apoptosis in the presence of both TNFA and IKI-1. Additionally, IKKB small interfering RNA transfected cells were more sensitive to the treatment of TNFA. The study suggests that the limited efficacy of TNFA in cancer treatment was due in part to the activation of NF-KB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFA may improve the efficacy of TNFA for certain tumor types. [Cancer Res 2008;68(22):9519-24]

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“…One possibility is suggested by the close chemical similarity between EP and pyruvate, a compound that is known to be an effective scavenger of reactive oxygen species (ROS) (Adickes and Andresen, 1943;Bunton, 1949;Melzer and Schmidt, 1988;Dobsak et al, 1999). An oxidizing environment, particularly in the cytosol, has been implicated in the activation of proinflammatory signaling molecules, such as NF-B (Schreck et al, 1992;Oka et al, 2000;Schoonbroodt et al, 2000;Livolsi et al, 2001;Rahman et al, 2001) and p38 mitogen-activated protein kinase . Accordingly, EP, by scavenging ROS, might inhibit activation of proinflammatory pathways induced by various stimuli.…”

mentioning

confidence: 99%

Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

Song

Kellum²,

Kaldas³

et al. 2003

J Pharmacol Exp Ther

119

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Ethyl pyruvate (EP), an effective scavenger of reactive oxygen species, is also an anti-inflammatory agent in a variety of in vivo and in vitro model systems. To gain a better understanding of the molecular basis for the anti-inflammatory effects of EP, we compared the pharmacological properties of EP and N-acetyl-L-cysteine (NAC), a well studied scavenger of reactive oxygen species and a precursor for the endogenous antioxidant glutathione (GSH). The studies were performed using RAW 264.7 murine macrophage-like cells that were stimulated with lipopolysaccharide (LPS). Although EP and NAC both inhibited LPS-induced nitric oxide and interleukin (IL)-6 secretion, the former compound was considerably more potent than the latter. EP markedly inhibited inducible nitric-oxide synthase, IL-6, and IL-10 mRNA induction, whereas the effects of NAC were minimal. EP inhibited LPS-induced nuclear factor-B DNA binding to a much greater extent than did NAC. Both compounds inhibited LPS-induced lipid peroxidation, but the two compounds had qualitatively different effects on cellular levels of GSH. Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cellpermeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.

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N‐Acetylcysteine suppresses TNF‐induced NF‐κB activation through inhibition of IκB kinases

Cited by 161 publications

References 46 publications

Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

IκBα Kinase Inhibitor IKI-1 Conferred Tumor Necrosis Factor α Sensitivity to Pancreatic Cancer Cells and a Xenograft Tumor Model

Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

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