Delayed treatment with diethyl maleate prevents E-selectin expression in human endothelial cells

Wei, Alice C.; Fan, Jia; Jones, Janet; Hamilton, Julia E.; Li, Yue Hua; Marshall, John C.; Rotstein, Ori D.

doi:10.1067/msy.1999.98929

Cited by 4 publications

(6 citation statements)

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“…Hence, depletion of the important intracellular antioxidant, glutathione (GSH), which shifts the intracellular redox milieu toward a more oxidized state, might interfere with binding to DNA by the activated NF-B complex through this mechanism. This idea is supported by results from several studies that document that LPS-or TNF-␣-induced inflammation and/or NF-B activation are downregulated by prior administration of pharmacological agents that promote depletion of cellular GSH stores (Nathens et al, 1996(Nathens et al, , 1998Jones et al, 1999;Wei et al, 1999;Kefer et al, 2001). Since pyruvate is known to react with cysteine to form an unstable thiazolidine adduct , it is conceivable that EP might function as a GSH-depleting agent and exert anti-inflammatory effects on this basis.…”

supporting

confidence: 66%

“…The results from several prior studies document that LPS-or TNF-␣-induced inflammation and/or NF-B activation is down-regulated by prior exposure of cells or animals to pharmacological agents that promote depletion of cellular GSH stores (Nathens et al, 1996(Nathens et al, , 1998Jones et al, 1999;Wei et al, 1999;Kefer et al, 2001). The basis for this pharmacology is thought to be enhanced formation of mixed disulfides involving critical cysteine residues in the proteins making up NF-B when the GSH/GSSG ratio is relatively low (Galter et al, 1994).…”

Section: Discussionmentioning

confidence: 96%

“…Alternatively, because incubating RAW 264.7 cells with GSH-Et (in the absence of LPS or EP) significantly increased intracellular levels of GSH (condition 2 versus condition 1 in Table 4), it is possible that the subtle proinflammatory effects of GSH-Et were caused by the same mechanism that has been offered here to explain the anti-inflammatory effects of EP. Thus, according to our proposed model, agents, such as EP or diethyl maleimide (Nathens et al, 1996(Nathens et al, , 1998Wei et al, 1999;Kefer et al, 2001), that decrease intracellular GSH concentration are anti-inflammatory; whereas an agent, such as GSH-Et, that increases cellular GSH concentration is proinflammatory.…”

Section: Discussionmentioning

confidence: 99%

“…Results from several prior studies indicate that LPS-induced NF-B activation, iNOS expression, and proinflammatory cytokine production are inhibited by agents that deplete intracellular levels of GSH (Buchmuller-Rouiller et al, 1995;Kang et al, 1999;Wang et al, 1999;Wei et al, 1999;Kefer et al, 2001). We hypothesized that the antiinflammatory effects of EP might occur as a result of this mechanism.…”

Section: Ep and Nac Exert Differential Effects On Intracellular Gsh Cmentioning

confidence: 98%

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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

120

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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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supporting

confidence: 66%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Ep and Nac Exert Differential Effects On Intracellular Gsh Cmentioning

confidence: 98%

See 2 more Smart Citations

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

120

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“…These decreased glutathione levels were associated with a diminished activation of NF-B DNA-binding activity in PAEC upon TNF-␣ activation. These findings are consistent with reports that diethyl maleate, a glutathione-depleting agent, attenuated NF-B DNA nuclear translocation and E-selectin expression in LPS-stimulated HUVECs (77) and that change of intracellular glutathione levels affects NF-B DNA-binding activity in human ECs (78). However, our data suggest that changes in intracellular glutathione do not explain the suppression of NF-B DNA-binding activity of PAEC in response to pretreatment with the NO donor, SNAP.…”

Section: Discussionsupporting

confidence: 82%

Effect of Redox Modulation on Xenogeneic Target Cells: The Combination of Nitric Oxide and Thiol Deprivation Protects Porcine Endothelial Cells from Lysis by IL-2-Activated Human NK Cells

Tsuyuki

Horvath‐Arcidiacono

Bloom

2001

The Journal of Immunology

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Evidence suggests that NK cells contribute to the pathogenesis of delayed rejection of vascularized xenografts, and NK cells have been suggested to participate in hyperacute xenograft rejection. Endothelial cells have been shown to be the primary target of the recipient’s immune responses that mediate both hyperacute and delayed xenograft rejection. Under conditions of oxidative stress induced by thiol deprivation, but not under normal conditions, pretreatment of porcine aortic endothelial cells (PAECs) with the NO donor, S-nitroso-N-acetyl-penicillamine, dramatically inhibited killing of PAEC target cells by IL-2-activated human NK cells. This same combined treatment reduced both surface expression and mRNA levels of E-selectin. Moreover, anti-E-selectin mAb, but not Ab to VCAM-1, protected PAEC from lysis by human IL-2-activated NK cells in a dose-dependent manner. These findings suggest that expression of porcine E-selectin is important for the cytotoxicity of PAEC mediated by activated human NK cells and may be involved in the redox-mediated modulation of that cytotoxicity. It is known that NF-κB activation is required for transcription of E-selectin, and the current data show that the suppression of E-selectin expression by S-nitroso-N-acetyl-penicillamine pretreatment and thiol deprivation was associated with reduced NF-κB DNA-binding activity in PAEC. These data suggest that the regulation of porcine E-selectin may be important for modulating delayed xenograft rejection and that manipulation of cellular redox systems may provide a means to protect xenogeneic endothelial cells from NK cell-mediated cytotoxicity.

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Diethylmaleate activates the transcription factor Pap1 by covalent modification of critical cysteine residues

Castillo

Ayté

Chiva

et al. 2002

Molecular Microbiology

114

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Summary During the last decade, much has been learnt about the mechanisms by which oxidative stress is perceived by aerobic organisms. The Schizosaccharomyces pombe Pap1 protein is a transcription factor localized at the cytoplasm, which accumulates in the nucleus in response to different inducers, such as the pro‐oxidant hydrogen peroxide (H2O2) or the glutathione‐depleting agent diethylmaleate (DEM). As described for other H2O2 sensors, our genetic data indicates that H2O2 reversibly oxidizes two cysteine residues in Pap1 (Cys278 and Cys501). Surprisingly, our studies demonstrate that DEM generates a non‐reversible modification of at least two cysteine residues located in or close to the nuclear export signal of Pap1 (Cys523 and Cys532). This modification impedes the interaction of the nuclear exporter Crm1 with the nuclear export signal located at the carboxy‐terminal domain of Pap1. Mass spectrometry data suggest that DEM binds to the thiol groups of the target cysteine residues through the formation of a thioether. Here we show that DEM triggers Pap1 nuclear accumulation by a novel molecular mechanism.

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Delayed treatment with diethyl maleate prevents E-selectin expression in human endothelial cells

Cited by 4 publications

References 0 publications

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

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

Effect of Redox Modulation on Xenogeneic Target Cells: The Combination of Nitric Oxide and Thiol Deprivation Protects Porcine Endothelial Cells from Lysis by IL-2-Activated Human NK Cells

Diethylmaleate activates the transcription factor Pap1 by covalent modification of critical cysteine residues

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