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Articles in PresS, published online ahead of print February 20, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00016.2002
Submitted on January 14, 2002
Accepted on February 7, 2002
-INDUCED NUCLEAR FACTOR 
B ACTIVATION AND APOPTOSIS IN HEPATOCYTES
1 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: Robert_Schwabe{at}med.unc.edu.
Nuclear factor B (NFB) prevents hepatocytes from undergoing apoptosis during development and liver regeneration. Mice with inactivated glycogen synthase kinase-3ß (GSK-3ß) die from hepatocyte apoptosis during development due to a defect in NFB activation (Hoeflich et al., Nature 406, 86-90). In this study, we determined the role of GSK-3 in TNF-induced NFB activation and cell death in primary hepatocytes. LiCl, an established inhibitor of GSK-3, sensitized primary rat hepatocytes towards TNF-mediated apoptosis resulting in 90% cell death after 24h. This was accompanied by increased caspase 8-like and 3-like activities, nuclear fragmentation and DNA laddering. LiCl treatment had no effect on IB degradation, IB kinase (IKK) activity, NFB binding activity and p65 nuclear import and export, but decreased transcription of the NFB-dependent iNOS gene and a NFB-driven reporter gene. The p65 sequence revealed four potential GSK-3 phosphorylation sites within its c-terminal transactivation domains and recombinant GSK-3ß phosphorylated GST-p65(354-551), but not GST-p65(1-354) in vitro. These results indicate that GSK-3 protects hepatocytes from TNF-induced apoptosis through p65 phosphorylation and upregulation of NFB transactivation.
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