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-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis1
*
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen, Germany;
Department of Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany; and
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Hannover, Germany.
TNF-
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-
. 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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