Document Detail


Differential caspase-9-dependent signaling pathway between tumor necrosis factor receptor- and Fas-mediated hepatocyte apoptosis in mice.
MedLine Citation:
PMID:  16420519     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND/AIMS: Two apoptosis signaling pathways, which are used by different cell types, are identified. The activation of caspases is critical for the apoptosis process. The aim of this study was to investigate the effects of the caspase-9 inhibitor Ac-LEHD-CHO on tumor necrosis factor receptor (TNFR)- and Fas-mediated hepatocyte apoptosis in vivo, in order to evaluate the similarities and distinctions between TNFR- and Fas-mediated signaling pathways. METHODS: BALB/c mice were intravenously injected with d-galactosamine (GalN, 20 mg/mouse)/tumor necrosis factor-alpha (TNF-alpha, 0.5 microg/mouse), or alphaFas (10 microg/mouse) 30 min after treatment with the caspase-9 inhibitor Ac-LEHD-CHO or pan-caspase inhibitor Z-VAD-fmk. Liver injury was assessed biochemically and histologically. Cytochrome c release and processing of procaspases in the liver were analyzed by Western blotting. Activities of caspases were measured using a fluorogenic peptide substrate. RESULTS: Pretreatment with Z-VAD-fmk prevented liver injury and hepatocyte apoptosis induced by either GalN/TNF-alpha or alphaFas. On the other hand, pretreatment with Ac-LEHD-CHO prevented GalN/TNF-alpha-induced hepatotoxicity and hepatocyte apoptosis but not alphaFas-induced liver injury and apoptosis. Both inhibitors reduced the activities of caspase-9 and -3 in the livers of mice administered by GalN/TNF-alpha. However, unlike Z-VAD-fmk, Ac-LEHD-CHO did not inhibit caspase-3 activation in alphaFas-treated mice, although this inhibitor attenuated caspase-9. CONCLUSION: Fas may rely on both caspase-8 activation (extrinsic pathway) and mitochondria (intrinsic pathway) to activate caspase-3. If the mitochondria-dependent pathway is blocked, the other pathway can compensate. In contrast, TNFR may mediate hepatocellular apoptosis mainly through the mitochondria-mediated caspase-9 activation pathway alone.
Authors:
Motohiro Imao; Masahito Nagaki; Motoaki Imose; Hisataka Moriwaki
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Liver international : official journal of the International Association for the Study of the Liver     Volume:  26     ISSN:  1478-3223     ISO Abbreviation:  Liver Int.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-01-19     Completed Date:  2006-05-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101160857     Medline TA:  Liver Int     Country:  England    
Other Details:
Languages:  eng     Pagination:  137-46     Citation Subset:  IM    
Affiliation:
First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Chloromethyl Ketones / pharmacology
Animals
Antigens, CD95 / pharmacology
Apoptosis / drug effects*,  physiology
Blotting, Western
Caspase 9
Caspases / metabolism*
Cysteine Proteinase Inhibitors / pharmacology*
Disease Models, Animal
Enzyme Activation
Galactosamine
Hepatocytes / cytology*,  drug effects,  metabolism
In Situ Nick-End Labeling
Male
Mice
Mice, Inbred BALB C
Random Allocation
Receptors, Tumor Necrosis Factor / metabolism*
Signal Transduction
Chemical
Reg. No./Substance:
0/Amino Acid Chloromethyl Ketones; 0/Antigens, CD95; 0/Cysteine Proteinase Inhibitors; 0/Receptors, Tumor Necrosis Factor; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 7535-00-4/Galactosamine; EC 3.4.22.-/Casp9 protein, mouse; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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