Inhibition of GSK3 differentially modulates NF-{kappa}B, CREB, AP-1 and {beta}-catenin signaling in hepatocytes, but fails to promote TNF-{alpha}-induced apoptosis
- Institute of Molecular Medicine and Cell Research, University of Freiburg (Germany)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg (Germany)
- DSM Nutritional Products 4303 Kaiseraugst (Switzerland)
- Gastroenterology, Department of Medicine, University Hospital Freiburg (Germany)
- Department of Pharmaceutical and Medicinal Chemistry, University of Tuebingen (Germany)
Glycogen synthase kinase-3 (GSK-3) is known to modulate cell survival and apoptosis through multiple intracellular signaling pathways. However, its hepatoprotective function and its role in activation of NF-{kappa}B and anti-apoptotic factors are poorly understood and remain controversial. Here we investigated whether inhibition of GSK-3 could induce apoptosis in the presence of TNF-{alpha} in primary mouse hepatocytes. We show that pharmacological inhibition of GSK-3 in primary mouse hepatocytes does not lead to TNF-{alpha}-induced apoptosis despite reduced NF-{kappa}B activity. Enhanced stability of I{kappa}B-{alpha} appears to be responsible for lower levels of nuclear NF-{kappa}B and hence reduced transactivation. Additionally, inhibition of GSK-3 was accompanied by marked upregulation of {beta}-catenin, AP-1, and CREB transcription factors. Stimulation of canonical Wnt signaling and CREB activity led to elevated levels of anti-apoptotic factors. Hence, survival of primary mouse hepatocytes may be caused by the activation and/or upregulation of other key regulators of liver homeostasis and regeneration. These signaling molecules may compensate for the compromised anti-apoptotic function of NF-{kappa}B and allow survival of hepatocytes in the presence of TNF-{alpha} and GSK-3 inhibition.
- OSTI ID:
- 21045962
- Journal Information:
- Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 6 Vol. 314; ISSN 0014-4827; ISSN ECREAL
- Country of Publication:
- United States
- Language:
- English
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