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Research ArticleArticle

Ebselen Protects Mice Against T Cell-Dependent, TNF-Mediated Apoptotic Liver Injury1

Gisa Tiegs, Sabine Küsters, Gerald Künstle, Hannes Hentze, Alexandra K. Kiemer and Albrecht Wendel
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 1098-1104;
Gisa Tiegs
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Sabine Küsters
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Gerald Künstle
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Hannes Hentze
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Alexandra K. Kiemer
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Albrecht Wendel
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Abstract

The seleno-organic drug ebselen (2-phenyl-1,2-benzoisoselenazol-3(2H)-one) has glutathione peroxidase-like activity, and inhibits lipoxygenases, oxidative burst of leukocytes, nitric oxide synthases, protein kinases and leukocyte migration. This study elaborates in vivoin mice hitherto unknown immunopharmacological properties of ebselen. The compound was comparatively investigated in two different T cell-dependent hepatic hyperinflammation models and in two alternative models of receptor-activated liver apoptosis. Mice orally pretreated with ebselen were dose-dependently protected from concanavalin A (ConA)-induced liver injury. In livers from ebselen-pretreated mice exposed to ConA, the nuclear antiapoptotic transcription factor NFκB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-α (TNF) was downregulated, while the ciculating amount of the anti-inflammatory cytokine interleukin-10 (IL-10) was increased. Ebselen protected also from liver injury induced by the superantigen staphylococcal enterotoxin B in galactosamine (GalN)-sensitized mice. Furthermore, ebselen protected the liver and enhanced circulating IL-10 in GalN-sensitized mice treated with recombinant TNF, i.e., the common distal mediator of ConA and SEB-induced hepatotoxicity. The activation of apoptosis-executing proteases, i.e., caspases, was blocked in livers of ebselen-treated mice following TNF receptor, but not following CD95 receptor activation. We propose a novel mechanism for the immunomodulatory properties of the drug and suggest that it might be useful in the therapy of T cell-mediated inflammatory disorders.

Footnotes

  • Send reprint requests to: Dr. Albrecht Wendel, Biochemical Pharmacology, University of Konstanz, PO Box 5560 M 667, D-78457 Konstanz, Germany. E-mail: Albrecht.Wendel{at}uni-konstanz.de

  • 1 This study was supported by Daiichi Seiyaku Co. Ltd., Tokyo, and by the Deutsche Forschungsgemeinschaft, grants We 686/18–1 and Ti 169/4–1.

  • Abbreviations:
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    ConA
    concanavalin A
    GalN
    d-galactosamine
    IFNγ
    interferon gamma
    IL
    interleukin
    SDH
    sorbitol dehydrogenase
    SEB
    Staphylococcusenterotoxin B
    Th
    T-helper cell
    TNF
    tumor necrosis factor-α
    z-VAD-fmk
    benzoyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.
    • Received December 22, 1997.
    • Accepted July 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Ebselen Protects Mice Against T Cell-Dependent, TNF-Mediated Apoptotic Liver Injury1

Gisa Tiegs, Sabine Küsters, Gerald Künstle, Hannes Hentze, Alexandra K. Kiemer and Albrecht Wendel
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1098-1104;

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Research ArticleArticle

Ebselen Protects Mice Against T Cell-Dependent, TNF-Mediated Apoptotic Liver Injury1

Gisa Tiegs, Sabine Küsters, Gerald Künstle, Hannes Hentze, Alexandra K. Kiemer and Albrecht Wendel
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1098-1104;
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