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J Biol Chem, Vol. 275, Issue 1, 705-712, January 7, 2000

Hepatocytes Sensitized to Tumor Necrosis Factor- 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^§, and Mark J. Czaja

From the  Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, ^§ IDUN Pharmaceuticals, Inc., La Jolla, California 92037, and the ^¶ Departments of Medicine, Biochemistry, and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

Hepatocytes can be sensitized to tumor necrosis factor (TNF)- toxicity by repression of NF-B activation or inhibition of RNA synthesis. To determine whether both forms of sensitization lead to TNF- cytotoxicity by similar mechanisms, TNF--induced cell death in RALA255-10G hepatocytes was examined following infection with an adenovirus, Ad5IB, that blocks NF-B activation or following cotreatment with actinomycin D (ActD). TNF- treatment of Ad5IB-infected cells resulted in 44% cell death within 6 h. ActD/TNF- 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 Ad5IB/TNF--induced cell death but did not inhibit ActD/TNF--induced apoptosis. A Fas-associated protein with death domain (FADD) dominant negative decreased Ad5IB/TNF-- and ActD/TNF--induced cell death by 81 and 47%, respectively. However, downstream events differed, since Ad5IB/TNF- but not ActD/TNF- treatment caused mitochondrial cytochrome c release. These results suggest that NF-B inactivation and inhibition of RNA synthesis sensitize RALA255-10G hepatocytes to TNF- toxicity through distinct cell death pathways that diverge below the level of FADD. ActD-induced hepatocyte sensitization to TNF- cytotoxicity occurs through a FADD-dependent, caspase-independent pathway of apoptosis.

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