Concanavalin A—induced T-cell—mediated hepatic injury in mice: The role of tumor necrosis factor

Abstract

Concanavalin A activates T lymphocytes in vitro and causes T-cell-dependent hepatic injury in mice. T lymphocytes were previously identified as effector cells of concanavalin A-induced liver injury. Here we report that hepatic injury is characterized by apoptotic cell death. On concanavalin A challenge, the cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-2, granulocyte macrophage-colony stimulating factor, and interferon-gamma were detectable in the circulation of the mice. Pretreatment of mice with anti-mouse TNF-alpha antiserum protected them from concanavalin A-induced liver injury. Nude mice failed to release TNF-alpha or interleukin-2 after concanavalin A challenge and were protected from liver injury. Lymph node cell transfer from responder mice to resistant nude mice resulted in susceptibility of the latter towards concanavalin A, i.e., to induction of cytokine release and hepatotoxicity. These experiments suggest that immunocompetent T cells play a pivotal role in concanavalin A-stimulated TNF-alpha release in vivo. After intravenous administration of fluorescein isothiocyanate-labeled concanavalin A to mice, the most fluorescence was found within the liver. In vitro, concanavalin A stimulation of separate cultures of mouse lymph node cells or nonparenchymal liver cells induced the release of minute amounts of TNF, whereas stimulation of cocultures of these cells resulted in production of substantial amounts of TNF-alpha. These findings may explain the hepatotropic effect of concanavalin A. In conclusion, T-cell-dependent concanavalin A-induced apoptotic liver injury in mice is related to immunological and cytokine-mediated disorders and possibly to autoreactive hepatic processes.

Protection from concanavalin A (Con A)-induced T cell-dependent hepatic lesions and modulation of cytokine release in mice by sodium fusidate

“…Our present observation that immunoinflammatory hepatitis can be induced in mice by a single i.v injection of Con A further confirms the original data by Tiegs' group [1,2], which were independently reproduced by others [3,8]. Most histological and immunopathogenic pathways described in those studies were also observed here.…”

“…An additional control group consisted of mice challenged only with PBS (Table 1). Because marked increases of transaminase activity along with severe histological signs of hepatic injuries have been reported to develop 8 h after Con A injection in these mice [1,2], the animals were killed after 8 h, and blood and livers were collected. Table 1.…”

Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice

“…These data are corroborated by a recent report from YodaMurakami and co-workers showing an increase of adiponectin in inflamed liver tissue induced by injection of CCl 4 [10]. ConA-induced hepatic inflammation is characterized by highly elevated systemic as well as hepatic TNF-a levels [11]. In addition, adiponectin has been shown to be a major antagonist of TNF-a production in several cell types [7,12].…”

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

“…ConA-induced hepatitis is also thought to be a model of immunologically induced hepatocyte injury, and its histological features resemble those of viral-or drug-induced acute hepatitis in humans. 1,7,[25][26][27][28][29][30] In this mode, hepatocyte cell death induced by ConA is caused by necrosis and apoptosis. Hence, apoptosis and Th1 cytokine release were thought to be key factors.…”

“…4 We also know that the stimulation of Fas on hepatocytes by anti-Fas antibodies causes severe damage to hepatocytes by apoptotic cell death. 31 Earlier results showed that liver necroapoptosis induced by ConA is mediated by TNF-a and IFN-g. 1,4,5,7,[25][26][27][28][29][30]32 On TNF-a receptor crosstalk, the death domain of the TNF-a receptor 1 associates with TNF receptor 1-associated protein (TRADD), causing Fas-associated death domain (FADD) recruitment. FADD in turn activates upstream caspase-8, and the effector caspases involved in apoptosis, caspase-9 and -3.…”