Hepatocytes sensitized to tumor necrosis factor-α cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways

Brett E. Jones, Chau R. Lo, Hailing Liu, Anu Srinivasan, Konrad Streetz, Karen L. Valentino, Mark J. Czaja

Research output: Contribution to journalArticle

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Abstract

Hepatocytes can be sensitized to tumor necrosis factor (TNF)-α toxicity by repression of NF-κB activation or inhibition of RNA synthesis. To determine whether both forms of sensitization lead to TNF-α cytotoxicity by similar mechanisms, TNF-α-induced cell death in RALA255-10G hepatocytes was examined following infection with an adenovirus, Ad5IκB, that blocks NF-κB activation or following cotreatment with actinomycin D (ActD). TNF-α treatment of Ad5IκB-infected cells resulted in 44% cell death within 6 h. ActD/TNF-α 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 Ad5IκB/TNF-α- induced cell death but did not inhibit ActD/TNF-α-induced apoptosis. A Fas- associated protein with death domain (FADD) dominant negative decreased Ad5IκB/TNF-αand ActD/TNF-α-induced cell death by 81 and 47%, respectively. However, downstream events differed, since Ad5IκB/TNF-α but not ActD/TNF-α treatment caused mitochondrial cytochrome c release. These results suggest that NF-κB inactivation and inhibition of RNA synthesis sensitize RALA255- 10G hepatocytes to TNF-α toxicity through distinct cell death pathways that diverge below the level of FADD. ActD-induced hepatocyte sensitization to TNF-α cytotoxicity occurs through a FADD-dependent, caspase-independent pathway of apoptosis.

Original languageEnglish (US)
Pages (from-to)705-712
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number1
DOIs
StatePublished - Jan 7 2000

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Cytotoxicity
Caspases
Hepatocytes
Tumor Necrosis Factor-alpha
Apoptosis
Dactinomycin
Cell death
Cell Death
Fas-Associated Death Domain Protein
Chemical activation
Toxicity
RNA
Adenoviridae Infections
Proteins
Caspase Inhibitors
Cytochromes c

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hepatocytes sensitized to tumor necrosis factor-α cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways. / Jones, Brett E.; Lo, Chau R.; Liu, Hailing; Srinivasan, Anu; Streetz, Konrad; Valentino, Karen L.; Czaja, Mark J.

In: Journal of Biological Chemistry, Vol. 275, No. 1, 07.01.2000, p. 705-712.

Research output: Contribution to journalArticle

Jones, Brett E. ; Lo, Chau R. ; Liu, Hailing ; Srinivasan, Anu ; Streetz, Konrad ; Valentino, Karen L. ; Czaja, Mark J. / Hepatocytes sensitized to tumor necrosis factor-α cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 1. pp. 705-712.
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