Universität zu Köln

Ehlken, Hanno, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Heinrichsdorff, Jan, Ochoa-Callejero, Laura ORCID: 0000-0001-5366-6613, Roskams, Tania ORCID: 0000-0002-2816-1530 and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2011). Hepatocyte IKK2 Protects Mdr2(-/-) Mice from Chronic Liver Failure. PLoS One, 6 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/-)) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-kappa B by expression of an I kappa B alpha super-repressor (I kappa B alpha SR) transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/-) mice, suggesting that NF-kappa B acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-kappa B by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-kappa B activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/-) mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/-) mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-) IKK2(Hep-KO) mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs. Conclusion: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ehlken, Hanno UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Heinrichsdorff, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ochoa-Callejero, Laura UNSPECIFIED orcid.org/0000-0001-5366-6613 UNSPECIFIED Roskams, Tania UNSPECIFIED orcid.org/0000-0002-2816-1530 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-487287
DOI:	10.1371/journal.pone.0025942
Journal or Publication Title:	PLoS One
Volume:	6
Number:	10
Date:	2011
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; MDR2-KNOCKOUT MICE; INDUCED APOPTOSIS; ACTIVATION; FIBROSIS; INFLAMMATION; DISEASE; HEPATOCARCINOGENESIS; CARCINOGENESIS; MECHANISMS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48728