TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf, Dominik; Hallmann, Rupert; Sass, Gabriele; Sixt, Michael; Küsters, Sabine; Fregien, Bastian; Trautwein, Christian; Tiegs, Gisa

doi:10.4049/jimmunol.166.2.1300

Cited by 109Liver physiology and pathologyCell Adhesion Molecules ResearchDrug-Induced Hepatotoxicity and Protection

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

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Wolf, Dominik, Hallmann, Rupert, Sass, Gabriele, Sixt, Michael, Küsters, Sabine, Fregien, Bastian, Trautwein, Christian, Tiegs, Gisa·2001·The Journal of Immunology

DOI 10.4049/jimmunol.166.2.1300

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Abstract

TNF-α has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1−/− and TNFR2−/− mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-γ. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1−/− and TNFR2−/− mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM−/− mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4+ T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism.

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Ccn1dm/dm mice are substantially resistant to concanavalin A-induced, TNF-α-dependent hepatocyte apoptosis.
“Ccn1dm/dm mice are substantially resistant to concanavalin A-induced, TNF-α-dependent hepatocyte apoptosis [107,108].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [108]

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Authors: Wolf, D., Hallmann, R., Sass, G., Sixt, M., Küsters, S., Fregien, B., Trautwein, C., & Tiegs, G.
Affiliations: Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg , Erlangen ,
Medizinische Hochschule Hannover (DE)
Corresponding author: Wolf, Dominik
Sass, Gabriele
Tiegs, Gisa
ORCID: Wolf, Dominik
Hallmann, Rupert
Sass, Gabriele
Sixt, Michael
Trautwein, Christian
Tiegs, Gisa
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2001-01
Volume: 166
Issue: 2
Pages: 1300-1307
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.166.2.1300
OpenAlex: W2022296058
Cited by: 109
References: 46
Citations by year: 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 6 · 2013: 4 · 2012: 3
FWCI: 6.46
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: TNF-α, TNFR1, TNFR2, adhesion molecules, ICAM-1, VCAM-1, E-selectin, hepatocyte death, receptor shedding, CD4+ T cells, acute liver injury, T cell activation
MeSH terms: Animals, Antibodies, Monoclonal, Cell Movement, Concanavalin A, Injections, Intraperitoneal, Injections, Intravenous, Liver, Male, Mice, Inbred BALB C, Recombinant Proteins, RNA, Messenger, Solubility, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Antigens, CD, Cell Adhesion Molecules, Up-Regulation, Lymphocyte Function-Associated Antigen-1, Cytokines, Liver Failure, Acute, Receptors, Tumor Necrosis Factor, Mice, Knockout, Intercellular Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, E-Selectin, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Mice, Chemical and Drug Induced Liver Injury

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TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

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