| Title | Hepatocytes sensitized to tumor necrosis factor-alpha cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways. | | Author(s) | Jones BE, Lo CR, Liu H, Srinivasan A, Streetz K, Valentino KL, Czaja MJ | | Institution | Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. | | Source | J Biol Chem 2000 Jan 7; 275(1):705-12. | | MeSH | Adaptor Proteins, Signal Transducing
Animals
Apoptosis
Carrier Proteins
Caspases
Cell Line
Comparative Study
Cytochrome c Group
Dactinomycin
Enzyme Activation
I-kappa B Proteins
Liver
NF-kappa B
Ploidies
Poly(ADP-ribose) Polymerases
Rats
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Signal Transduction
Tumor Necrosis Factor-alpha
| | Abstract | Hepatocytes can be sensitized to tumor necrosis factor (TNF)-alpha toxicity by repression of NF-kappaB activation or inhibition of RNA synthesis. To determine whether both forms of sensitization lead to TNF-alpha cytotoxicity by similar mechanisms, TNF-alpha-induced cell death in RALA255-10G hepatocytes was examined following infection with an adenovirus, Ad5IkappaB, that blocks NF-kappaB activation or following cotreatment with actinomycin D (ActD). TNF-alpha treatment of Ad5IkappaB-infected cells resulted in 44% cell death within 6 h. ActD/TNF-alpha induced no death within 6 h but did lead to 37% cell death by 24 h. In both instances, cell death occurred by apoptosis and was associated with caspase activation, although caspase activation in ActD-sensitized cells was delayed. CrmA and chemical caspase inhibitors blocked Ad5IkappaB/TNF-alpha-induced cell death but did not inhibit ActD/TNF-alpha-induced apoptosis. A Fas-associated protein with death domain (FADD) dominant negative decreased Ad5IkappaB/TNF-alpha- and ActD/TNF-alpha-induced cell death by 81 and 47%, respectively. However, downstream events differed, since Ad5IkappaB/TNF-alpha but not ActD/TNF-alpha treatment caused mitochondrial cytochrome c release. These results suggest that NF-kappaB inactivation and inhibition of RNA synthesis sensitize RALA255-10G hepatocytes to TNF-alpha toxicity through distinct cell death pathways that diverge below the level of FADD. ActD-induced hepatocyte sensitization to TNF-alpha cytotoxicity occurs through a FADD-dependent, caspase-independent pathway of apoptosis. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 10617670 |
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