Universität zu Köln

Bergmann, Juri, Mueller, Miryam, Baumann, Niklas, Reichert, Manuel, Heneweer, Carola, Bolik, Julia, Luecke, Karsten, Gruber, Sabine, Carambia, Antonella, Boretius, Susanne, Leuschner, Ivo, Becker, Thomas, Rabe, Bjoern, Herkel, Johannes ORCID: 0000-0001-9055-9999, Wunderlich, F. Thomas, Mittruecker, Hans-Willi, Rose-John, Stefan ORCID: 0000-0002-7519-3279 and Schmidt-Arras, Dirk ORCID: 0000-0002-1072-7495 (2017). IL-6 Trans-Signaling Is Essential for the Development of Hepatocellular Carcinoma in Mice. Hepatology, 65 (1). S. 89 - 104. HOBOKEN: WILEY. ISSN 1527-3350

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Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans-signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances beta-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy) benzene model of HCC. Conclusion: IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bergmann, Juri UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Miryam UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichert, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Heneweer, Carola UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolik, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Luecke, Karsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruber, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Carambia, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED Boretius, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Leuschner, Ivo UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Rabe, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Herkel, Johannes UNSPECIFIED orcid.org/0000-0001-9055-9999 UNSPECIFIED Wunderlich, F. Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Mittruecker, Hans-Willi UNSPECIFIED UNSPECIFIED UNSPECIFIED Rose-John, Stefan UNSPECIFIED orcid.org/0000-0002-7519-3279 UNSPECIFIED Schmidt-Arras, Dirk UNSPECIFIED orcid.org/0000-0002-1072-7495 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-243437
DOI:	10.1002/hep.28874
Journal or Publication Title:	Hepatology
Volume:	65
Number:	1
Page Range:	S. 89 - 104
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LIVER-CANCER; P53; INTERLEUKIN-6; CATENIN; PROTEIN; CIRRHOSIS; CYTOKINE; COMPLEX; TUMORIGENESIS; INFLAMMATION Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24343