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.