Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury

Luedde, Tom; Assrnus, Ulnke; Wüstefeld, Torsten; Vilsendori, Andreas Meyer Zu; Roskams, Tania; Schmidt-supprian, Mark; Rajewsky, Klaus; Brenner, DavidA.; Manns, Michael P.; Pasparakis, Manolis; Trautwein, Christian; Assmus, Ulrike; Wüstefeld, Torsten; Meyer zu Vilsendorf, Andreas; Brenner, David A
April 2005
Journal of Clinical Investigation;Apr2005, Vol. 115 Issue 4, p849
Academic Journal
journal article
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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