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

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.

• Authors: Tom Luedde, Ulrike Assmus, Torsten Wüstefeld, Andreas Meyer zu Vilsendorf, Tania Roskams, Mark Schmidt-Supprian, Klaus Rajewsky, David A Brenner, Michael P Manns, Manolis Pasparakis, Christian Trautwein
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 4 Pg. 849-59 (Apr 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15776110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multiprotein Complexes
• NF-kappa B
• Protein Subunits
• Tumor Necrosis Factor-alpha
• Concanavalin A
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Protein Serine-Threonine Kinases
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Animals
• Apoptosis (physiology)
• Cells, Cultured
• Concanavalin A (pharmacology)
• Hepatocytes (cytology, drug effects, physiology)
• I-kappa B Kinase
• Liver (cytology, pathology, physiology)
• Male
• Mice
• Mice, Knockout
• Multiprotein Complexes
• NF-kappa B (metabolism)
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Protein Subunits (genetics, metabolism)
• Reperfusion Injury
• Tumor Necrosis Factor-alpha (pharmacology)