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¹ Department of Internal Medicine III, University Hospital (RWTH) Aachen, Aachen 5205, Germany
² Human Genetics Division, Southampton University School of Medicine, Southampton General Hospital, Southampton SO16, England, UK
³ Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905
⁴ Department of Pathology, Catholic University of Leuven, Leuven B-3000, Belgium

CORRESPONDENCE Christian Trautwein: ctrautwein{at}ukaachen.de

Nuclear factor B (NF-B) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-B activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMO^hepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMO^hepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMO^hepa livers. Interestingly, depletion of the NK1.1⁺ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMO^hepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMO^hepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient^–/– mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMO^hepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.

Abbreviations used: ConA, concanavalin A; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; JNK, c-Jun N-terminal kinase; MNC, mononuclear cell; mRNA, messenger RNA; TRAIL, TNF-related apoptosis-inducing ligand.

© 2009 Beraza et al.
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