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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 2

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Nemo, but not Ikk2, deletion results in apoptotic cell death in the live...
Nemo, but not Ikk2, deletion results in apoptotic cell death in the liver upon TNF-α stimulation. (A) Ikk2Δhepa, Ikk2Δ, or NemoΔ mice and their respective control litter mates (Ikk2f/f or Nemof/f) were injected intravenously with 6 μg/kg of recombinant TNF-α or intraperitoneally with LPS (100 μg/kg) and GalN (800 mg/kg) (right top panel). Liver injury was measured by determining ALT levels. Values are mean ± SD for independent animals (n = 6). Single asterisks indicate statistical significance with P < 0.01 versus Nemof/f control mice. All NemoΔ mice died between 2 and 3 hours after TNF-α stimulation from hepatic failure. (B) TUNEL staining of liver slides before and 2 hours after TNF-α stimulation showing clear positive staining in NemoΔ, but not in Ikk2Δhepa mice. Results are representative of those obtained in mice (n = 6). Original magnification, × 40. (C) Detection of caspase 3–like activity by an enzymatic, fluorometric assay from whole liver protein lysates at different time points after TNF-α stimulation in Ikk2Δhepa, NemoΔ, and control littermates. Values are mean ± SD for independent animals (n = 6). (D) ALT levels as markers for liver injury at different time points following ConA injection into Ikk2Δhepa and Ikk2f/f mice. Values are mean ± SD for independent animals (n = 6). (E) ALT levels following Fas-stimulating Jo-2 injection into Ikk2Δhepa and Ikk2f/f mice. Values are mean ± SD for independent animals (n = 6). U/l, units per liter; AFC, 7-amino-trifluoromethyl coumarin.

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

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