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Activation and function of hepatocyte NF‐κB in postischemic liver injury
Author(s) -
Lentsch Alex B.
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20779
Subject(s) - iκb kinase , apoptosis , hepatocyte , conditional gene knockout , liver injury , reperfusion injury , tumor necrosis factor alpha , knockout mouse , nf κb , medicine , nfkb1 , cancer research , inflammation , immunology , pharmacology , ischemia , chemistry , receptor , biochemistry , transcription factor , in vitro , gene , phenotype
The inhibitor of NF‐κB (I‐κB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF‐κB essential modulator (NEMO), and is involved in the activation of NF‐κB 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‐κB or increased apoptosis after TNF‐alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF‐κB 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.