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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 Article has an altmetric score of 3

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

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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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Figure 7

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The pharmacological IKK2 inhibitor AS602868 protects mice from liver inj...
The pharmacological IKK2 inhibitor AS602868 protects mice from liver injury due to hepatic I/R. (A) C57BL6 mice received an oral administration of 150 μl of the IKK2 inhibitor AS602868 (10 μg/g body weight) or the vehicle substance (control) at 20 hours and 2 hours before stimulation with 6 μg/kg recombinant TNF-α. Evaluation of serum ALT levels at the indicated time points after TNF-α stimulation showing no significant difference between treated and untreated animals. (B) NF-κB EMSA using 5 μg of nuclear protein extracts from animals treated with AS602868 or control. (C) Serum AST and ALT levels were measured at the indicated time points after reperfusion in mice that were pretreated with AS602868 or vehicle substance (control) and had undergone partial I/R. Values are mean ± SD for independent animals (n = 4). The asterisk indicates statistical significance with P < 0.05 versus control mice. (D) H&E staining of liver slides at 6 hours after reperfusion from control mice and mice treated with AS602868. Original magnification, ×20. The area of necrotic parenchymal surface was measured and quantified (right panel). Values are mean ± SD for independent animals (n = 4). The double asterisk indicates statistical significance with P < 0.01 versus control mice. (E) Quantification of PMN leukocytes per high power field (×40) at 6 hours after reperfusion. Values are mean ± SD for independent animals (n = 4). The hatch mark indicates statistical significance with P < 0.001 versus control mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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