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- Title:
Genetic inactivation of RelA/p65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro.
- Document type:
- In Vitro; Journal Article; Research Support, Non-U.S. Gov't
- Author(s):
- Geisler, F; Algul, H; Paxian, S; Schmid, RM
- Abstract:
- BACKGROUND & AIMS: The transcription factor nuclear factor (NF)-kappaB plays a critical role in mediating survival of hepatocytes in response to tumor necrosis factor (TNF)-alpha during development because mice deficient for the NF-kappaB subunit RelA/p65 die in utero because of TNF-induced liver apoptosis. For the adult liver, conflicting concepts exist as to whether soluble TNF can trigger apoptosis when NF-kappaB activation is impaired. By creating a mouse model in which the transactivating NF-kappaB subunit RelA/p65 can be genetically inactivated in hepatocytes using the Cre/lox system, we sought to clarify the role of NF-kappaB in TNF-mediated hepatocyte apoptosis. METHODS: Deletion of RelA/p65 in the liver was achieved using an inducible conditional knockout system (rela(F/F)MxCre mice) or, hepatocyte-specifically, using a developmental conditional knockout system (rela(F/F)AlbCre mice). RESULTS: Disruption of RelA/p65 rendered mice sensitive to lethal liver injury upon TNF administration. Primary RelA/p65-deficient hepatocytes showed no NF-kappaB activation and undergo rapid apoptosis after TNF treatment. In contrast, hepatocytes deficient for I kappa B-kinase beta (IKK beta), displayed residual NF-kappaB activity and consecutively only mild apoptosis in response to TNF. TNF-induced apoptosis in RelA/p65-deficient hepatocytes was accompanied by prolonged activation of c-jun activating kinase (JNK) and rapid, largely proteasome-independent elimination of the long splice form of the antiapoptotic cellular FLICE inhibitor protein (c-FLIP(L)). Gene silencing of caspase-8, caspase-inhibitors, inhibition of JNK, or administration of antioxidants inhibited apoptosis and elimination of c-FLIP(L). CONCLUSIONS: RelA/p65 is essential for TNF-induced NF-kappaB activation in adult hepatocytes. Genetic deletion of a functional RelA/p65 sensitizes these cells to apoptosis in response to soluble TNF in vivo and in vitro.
- Journal title abbreviation:
- Gastroenterology
- Year:
- 2007
- Journal volume:
- 132
- Journal issue:
- 7
- Pages contribution:
- 2489-503
- Language:
- eng
- Fulltext / DOI:
- doi:10.1053/j.gastro.2007.03.033
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/17570221
- Print-ISSN:
- 0016-5085
- TUM Institution:
- II. Medizinische Klinik und Poliklinik (Gastroenterologie)
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