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

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.

In vivoregulation of inducible NO synthase in immune-mediated liver injury in mice

“…7 Hence, TNFR1Ϫ/Ϫ as well as TNFR2Ϫ/Ϫ mice do not release transaminases on con A challenge. 7 However, TNFR2Ϫ/Ϫ mice are protected despite the fact that they are still able to express cytokines, 7 adhesion molecules, 40 and, as shown in this study, iNOS.…”

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…Bone marrow transfer studies using CXCL16-deficient mice are warranted to ascertain the respective contributions of infiltrating versus resident renal cells toward the renal expression of CXCL16 (and the other implicated molecules) during immune nephritis. Although these 4 molecules have been discussed as independent entities, it is certainly possible that they may be coordinately regulated during disease, and there is some evidence to support this possibility (39)(40)(41).…”

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

“…Betulin reduces serum levels of IFN-γ, TNF-α, and IL-6 in mice with hepatitis Several lines of evidence suggest that IFN-γ [16,17] , TNF-α [18,19] , IL-4 [20] , and IL-17 [21,22] promote hepatic damage, whereas IL-10 [23] protects the liver from injury, and IL-6 [18] has varying effects depending on the stage of Con A-induced hepatitis at which it is present. To ascertain whether betulin interfered with the systemic levels of these cytokines, we examined the serum levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17 by using a CBA kit.…”

“…In Con A-induced hepatitis, the inflammatory response is responsible for liver damage and is mainly driven by proinflammatory Th1 cytokines. High levels of proinflammatory cytokines such as TNF-α [18,19] and IFN-γ [16] have been shown to promote the progress of this disease. In addition, neutralizing or knocking out the secretion of these cytokines leads to animal resistance to Con A-induced hepatic damage.…”