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Am J Physiol Cell Physiol 275: C1058-C1066, 1998;
0363-6143/98 $5.00
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Vol. 275, Issue 4, C1058-C1066, October 1998

NF-kappa B inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis

Yang Xu1,2, Shani Bialik1,3, Brett E. Jones1,2, Yuji Iimuro4, Richard N. Kitsis1,3, Anu Srinivasan5, David A. Brenner4, and Mark J. Czaja1,2

Departments of 1 Medicine and 3 Cell Biology and 2 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461; 4 Departments of Medicine and of Biochemistry and Biophysics and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599; and 5 IDUN Pharmaceuticals, Inc., La Jolla, California 92037

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-kappa B (NF-kappa B) 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-kappa B-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-kappa B activation but decreased NF-kappa B-dependent gene expression. Expression of an Ikappa B 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-kappa B activation was blocked. Although apoptosis was blocked by the NF-kappa B-dependent factor nitric oxide (NO), inhibition of endogenous NO production did not sensitize cells to TNF-alpha -induced cytotoxicity. Thus NF-kappa B 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-kappa B activation inhibits this death pathway.

caspases; nitric oxide; inducible nitric oxide synthase; liver; hydrogen peroxide


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