Article: article from journal or magazin.
Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice.
Tissue transglutaminase (TG2) is a protein cross-linking enzyme known to be expressed by hepatocytes and to be induced during the in vivo hepatic apoptosis program. TG2 is also a G protein that mediates intracellular signaling by the alpha-1b-adrenergic receptor (AR) in liver cells. Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti-Fas antibodies to mice causes both disseminated endothelial cell apoptosis and fulminant hepatic failure. Here we report that an intraperitoneal dose of anti-Fas antibodies, which is sublethal for wild-type mice, kills all the TG2 knock-out mice within 20 hours. Although TG2-/- thymocytes exposed to anti-Fas antibodies die at the same rate as wild-type mice, TG2-/- hepatocytes show increased sensitivity toward anti-Fas treatment both in vivo and in vitro, with no change in their cell surface expression of Fas, levels of FLIP(L) (FLICE-inhibitory protein), or the rate of I-kappaBalpha degradation, but a decrease in the Bcl-xL expression. We provide evidence that this is the consequence of the impaired AR signaling that normally regulates the levels of Bcl-xL in the liver. In conclusion, our data suggest the involvement of adrenergic signaling pathways in the hepatic regeneration program, in which Fas ligand-induced hepatocyte proliferation with a simultaneous inhibition of the Fas-death pathway plays a determinant role.
Animals, Antibodies/pharmacology, Antigens, CD95/genetics, Antigens, CD95/immunology, Apoptosis/physiology, Cell Death, Cell Division, Cell Survival/drug effects, Cells, Cultured, GTP-Binding Proteins/deficiency, GTP-Binding Proteins/genetics, Hepatocytes/cytology, Hepatocytes/drug effects, Liver Regeneration/physiology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, T-Lymphocytes/cytology, T-Lymphocytes/immunology, Transglutaminases/deficiency, Transglutaminases/genetics
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