Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury.
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.
Luedde
Tom
T
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Assmus
Ulrike
U
Wüstefeld
Torsten
T
Meyer zu Vilsendorf
Andreas
A
Roskams
Tania
T
Schmidt-Supprian
Mark
M
Rajewsky
Klaus
K
Brenner
David A
DA
Manns
Michael P
MP
Pasparakis
Manolis
M
Trautwein
Christian
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051550:I-kappa B Kinase; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D046912:Multiprotein Complexes; D016328:NF-kappa B; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse