Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor.
Excessive activity of the Fas system in the liver is an essential event and contributor to fulminant hepatic failure, whose prognosis is extremely poor with high mortality due to lack of effective therapy. Administration of agonistic anti-Fas antibody to mice rapidly led to massive liver apoptosis and fulminant hepatic failure. In contrast, administration of human recombinant hepatocyte growth factor (HGF) abrogated Fas-induced massive liver apoptosis and the lethal hepatic failure. Addition of anti-Fas antibody to hepatocytes in primary culture induced cell death, but Fas-mediated cell death was potently suppressed by HGF. HGF strongly induced Bcl-xL expression and subsequently blocked Fas-mediated signaling pathway upstream of CPP32 in the liver. These results implicate a potential therapeutic usage of HGF for treatment of fulminant hepatic failure.
Kosai
K
K
Department of Oncology, Osaka University Medical School, Japan.
Matsumoto
K
K
Nagata
S
S
Tsujimoto
Y
Y
Nakamura
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D008024:Ligands; D008099:Liver / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D017228:Hepatocyte Growth Factor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases