9755059

pubmed:Citation

4 Pt 1

Toxins convert the hepatocellular response to tumor necrosis factor-alpha (TNF-alpha) stimulation from proliferation to cell death, suggesting that hepatotoxins somehow sensitize hepatocytes to TNF-alpha toxicity. Because nuclear factor-kappaB (NF-kappaB) activation confers resistance to TNF-alpha cytotoxicity in nonhepatic cells, the possibility that toxin-induced sensitization to TNF-alpha killing results from inhibition of NF-kappaB-dependent gene expression was examined in the RALA rat hepatocyte cell line sensitized to TNF-alpha cytotoxicity by actinomycin D (ActD). ActD did not affect TNF-alpha-induced hepatocyte NF-kappaB activation but decreased NF-kappaB-dependent gene expression. Expression of an IkappaB superrepressor rendered RALA hepatocytes sensitive to TNF-alpha-induced apoptosis in the absence of ActD. Apoptosis was blocked by caspase inhibitors, and TNF-alpha treatment led to activation of caspase-2, caspase-3, and caspase-8 only when NF-kappaB activation was blocked. Although apoptosis was blocked by the NF-kappaB-dependent factor nitric oxide (NO), inhibition of endogenous NO production did not sensitize cells to TNF-alpha-induced cytotoxicity. Thus NF-kappaB activation is the critical intracellular signal that determines whether TNF-alpha stimulates hepatocyte proliferation or apoptosis. Although exogenous NO blocks RALA hepatocyte TNF-alpha cytotoxicity, endogenous production of NO is not the mechanism by which NF-kappaB activation inhibits this death pathway.

eng

IM

MEDLINE

0002-9513

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NLM

C1058-66

pubmed-meshheading:9755059-Animals, pubmed-meshheading:9755059-Apoptosis, pubmed-meshheading:9755059-Caspases, pubmed-meshheading:9755059-Cell Division, pubmed-meshheading:9755059-Cell Line, pubmed-meshheading:9755059-Cell Survival, pubmed-meshheading:9755059-Cysteine Proteinase Inhibitors, pubmed-meshheading:9755059-DNA, pubmed-meshheading:9755059-DNA-Binding Proteins, pubmed-meshheading:9755059-Gene Expression Regulation, pubmed-meshheading:9755059-I-kappa B Proteins, pubmed-meshheading:9755059-NF-kappa B, pubmed-meshheading:9755059-Nitric Oxide, pubmed-meshheading:9755059-Nitric Oxide Donors, pubmed-meshheading:9755059-Penicillamine, pubmed-meshheading:9755059-Rats, pubmed-meshheading:9755059-Recombinant Proteins, pubmed-meshheading:9755059-S-Nitroso-N-Acetylpenicillamine, pubmed-meshheading:9755059-Thymidine, pubmed-meshheading:9755059-Transfection, pubmed-meshheading:9755059-Tumor Necrosis Factor-alpha

NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't