Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury.
Standard
Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury. / Tiegs, Gisa; Küsters, S; Künstle, G; Hentze, H; Kiemer, A K; Wendel, A.
In: J PHARMACOL EXP THER, Vol. 287, No. 3, 3, 1998, p. 1098-1104.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury.
AU - Tiegs, Gisa
AU - Küsters, S
AU - Künstle, G
AU - Hentze, H
AU - Kiemer, A K
AU - Wendel, A
PY - 1998
Y1 - 1998
N2 - 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 vivo in 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 NFkappaB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-alpha (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.
AB - 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 vivo in 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 NFkappaB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-alpha (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.
KW - Animals
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Enzyme Activation
KW - NF-kappa B/metabolism
KW - Caspases/metabolism
KW - Concanavalin A
KW - Enterotoxins
KW - Azoles/pharmacology
KW - Immunosuppressive Agents/pharmacology
KW - Liver/drug effects/metabolism/pathology
KW - Liver Failure/prevention & control
KW - Organoselenium Compounds/pharmacology
KW - T-Lymphocytes/drug effects/immunology
KW - Tumor Necrosis Factor-alpha/immunology/metabolism/pharmacology
KW - Animals
KW - Mice
KW - Mice, Inbred BALB C
KW - Apoptosis
KW - Enzyme Activation
KW - NF-kappa B/metabolism
KW - Caspases/metabolism
KW - Concanavalin A
KW - Enterotoxins
KW - Azoles/pharmacology
KW - Immunosuppressive Agents/pharmacology
KW - Liver/drug effects/metabolism/pathology
KW - Liver Failure/prevention & control
KW - Organoselenium Compounds/pharmacology
KW - T-Lymphocytes/drug effects/immunology
KW - Tumor Necrosis Factor-alpha/immunology/metabolism/pharmacology
M3 - SCORING: Journal article
VL - 287
SP - 1098
EP - 1104
JO - J PHARMACOL EXP THER
JF - J PHARMACOL EXP THER
SN - 0022-3565
IS - 3
M1 - 3
ER -