Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury.
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.
Tiegs
G
G
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Germany.
Küsters
S
S
Künstle
G
G
Hentze
H
H
Kiemer
A K
AK
Wendel
A
A
D000818:Animals; D017209:Apoptosis; D001393:Azoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D003208:Concanavalin A; D004768:Enterotoxins; D004789:Enzyme Activation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D054833:Isoindoles; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
D001393:Azoles; D004768:Enterotoxins; D007166:Immunosuppressive Agents; D054833:Isoindoles; D016328:NF-kappa B; D016566:Organoselenium Compounds; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; C031818:enterotoxin B, staphylococcal; C042986:ebselen; D020169:Caspases