Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury
Tom Luedde, … , Manolis Pasparakis, Christian Trautwein
Tom Luedde, … , Manolis Pasparakis, Christian Trautwein
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):849-859. https://doi.org/10.1172/JCI23493.
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Article Hepatology

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-κB (I-κB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-κB essential modulator (NEMO), and is involved in the activation of NF-κB 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-κB or increased apoptosis after TNF-α stimulation whereas conditional NEMO knockout resulted in complete block of NF-κB 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

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Ikk2 deletion in hepatocytes protects against liver injury and inflammat...
Ikk2 deletion in hepatocytes protects against liver injury and inflammation after hepatic I/R. (A) Ikk2Δhepa and Ikk2f/f control mice underwent a procedure of partial hepatic ischemia lasting for 60 minutes, which was followed by reperfusion. Serum AST and ALT levels were measured at the indicated time points before the procedure and after reperfusion as markers for liver injury. Values are mean ± SD for independent animals (n = 8). Asterisks indicate statistical significance: *P < 0.02 versus Ikk2f/f control mice; **P < 0.05 versus Ikk2f/f control mice. (B) H&E staining of liver slides from Ikk2f/f and Ikk2Δhepa mice at 6 hours and 24 hours after reperfusion. N, necrotic area (arrows indicate margins of necrotic areas; P, portal vein; C, central vein. Results are representative of those obtained in 8 mice. Original magnification, ×20. The area of necrotic parenchymal surface was measured and quantified (right panel). Values are mean ± SD for independent animals (n = 4). Hatch mark indicates statistical significance: P < 0.01 versus Ikk2f/f control mice. (C) Quantification of PMN leukocytes per high power field (×40) at different time points after reperfusion. Values are mean ± SD for independent animals (n = 4). Double hatch marks indicate statistical significance: P < 0.001 versus Ikk2f/f control mice.