Universität zu Köln

Wroblewski, Raluca, Armaka, Marietta, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Walczak, Henning ORCID: 0000-0002-6312-4591, Mittruecker, Hans-Willi, Schramm, Christoph, Lohse, Ansgar W., Kollias, George ORCID: 0000-0003-1867-3150 and Ehlken, Hanno (2016). Opposing Role of Tumor Necrosis Factor Receptor 1 Signaling in T Cell-Mediated Hepatitis and Bacterial Infection in Mice. Hepatology, 64 (2). S. 508 - 522. HOBOKEN: WILEY-BLACKWELL. ISSN 1527-3350

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Abstract

Death receptor (DR) ligands such as tumor necrosis factor (TNF) have been identified as fundamental mediators of liver damage both in mouse models and in humans. While the essential site of function of DR signaling is conceivably the hepatocyte, a systematic analysis is missing. Using mice with conditional gene ablation, we analyzed the tissue-specific function of DR signaling in T cell-dependent (concanavalin A) and independent (lipopolysaccharide/galactosamine) hepatitis and in models of bacterial infection (Listeria monocytogenes, lipopolysaccharide). We report that lipopolysaccharide/galactosamine-induced liver injury depends on hepatocyte-intrinsic TNF receptor 1 (p55, TNFR1). In contrast, we show that T cell-induced hepatitis was independent of TNFR1 signaling in hepatocytes, T cells, or endothelial cells. Moreover, T cell-induced hepatitis was independent of hepatocyte-intrinsic Fas-associated protein with death domain, TNF-related apoptosis-inducing ligand receptor, or Fas signaling. Instead, concanavalin A-induced hepatitis was completely prevented in mice with myeloid-derived cell (MDC)-specific deletion of TNFR1. Significantly, however, mice lacking TNFR1 in MDCs succumbed to listeria infection, although they displayed similar sensitivity toward endotoxin-induced septic shock when compared to control mice. These results suggest that TNFR1 signaling in MDCs is a critical mediator of both the detrimental and the protective functions of TNF in T cell-induced hepatitis and bacterial infection, respectively. Conclusion: The critical site of action of DRs is completely dependent on the nature of hepatitis; the data specify MDCs as the essential cell type of TNFR1 function in T cell-mediated hepatitis and in the response to listeria, thereby identifying the opposing role of MDC TNFR1 in autoimmunity and bacterial infection.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wroblewski, Raluca UNSPECIFIED UNSPECIFIED UNSPECIFIED Armaka, Marietta UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Walczak, Henning UNSPECIFIED orcid.org/0000-0002-6312-4591 UNSPECIFIED Mittruecker, Hans-Willi UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohse, Ansgar W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kollias, George UNSPECIFIED orcid.org/0000-0003-1867-3150 UNSPECIFIED Ehlken, Hanno UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-268495
DOI:	10.1002/hep.28551
Journal or Publication Title:	Hepatology
Volume:	64
Number:	2
Page Range:	S. 508 - 522
Date:	2016
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1527-3350
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 INDUCED LIVER-INJURY; CONCANAVALIN-A; TNF-ALPHA; HEPATOCELLULAR-CARCINOMA; TRANSGENIC MOUSE; CRE-RECOMBINASE; EXPRESSION; APOPTOSIS; DEATH; JNK Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26849