Title: Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury
Authors: Luedde, Tom ×
Assmus, Ulrike
Wüstefeld, Torsten
Meyer zu Vilsendorf, Andreas
Roskams, Tania
Schmidt-Supprian, Mark
Rajewsky, Klaus
Brenner, David A
Manns, Michael P
Pasparakis, Manolis
Trautwein, Christian #
Issue Date: Apr-2005
Series Title: Journal of Clinical Investigation vol:115 issue:4 pages:849-59
Abstract: The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Cell & Tissue Research
× corresponding author
# (joint) last author

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