Universität zu Köln

Ehlken, H., Krishna-Subramanian, S., Ochoa-Callejero, L., Kondylis, V., Nadi, N. E., Straub, B. K., Schirmacher, P., Walczak, H., Kollias, G. and Pasparakis, M. ORCID: 0000-0002-9870-0966 (2014). Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ., 21 (11). S. 1721 - 1733. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5403

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Abstract

Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKK gamma, a subunit of the I kappa B kinase (IKK) complex that is essential for the activation of canonical NF-kappa B signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMOLPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMOLPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMOLPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMO-deficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMOLPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMOLPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMOLPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ehlken, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krishna-Subramanian, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ochoa-Callejero, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nadi, N. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Straub, B. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schirmacher, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Walczak, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kollias, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, M. UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-425049
DOI:	10.1038/cdd.2014.83
Journal or Publication Title:	Cell Death Differ.
Volume:	21
Number:	11
Page Range:	S. 1721 - 1733
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; GAMMA-DEFICIENT MICE; INCONTINENTIA PIGMENTI; PROTECTS MICE; INFLAMMATION; HEPATOCARCINOGENESIS; DELETION; CANCER; INJURY; DEGENERATION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/42504