Deletion of IKK2 in Hepatocytes Does Not Sensitize These Cells to TNF-induced Apoptosis but Protects from Ischemia/reperfusion Injury

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2005 Mar 19

PMID 15776110

Citations 62

Authors

Tom Luedde

Ulrike Assmus

Torsten Wustefeld

Andreas Meyer Zu Vilsendorf

Tania Roskams

Mark Schmidt-Supprian

Klaus Rajewsky

David A Brenner

Michael P Manns

Manolis Pasparakis

Christian Trautwein

Affiliations

Soon will be listed here.

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.

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