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 lym-phocytes 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 tu-mor necrosis factor-a (TNFa), interleukin-2, granulocyte macrophage-colony stimulating factor, and interferon-y were detectable in the circulation of the mice. Pre-treatment of mice with anti-mouse TNF-a antiserum pro-tected them from concanavalin A-induced liver injury. Nude mice failed to release TNF-a 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 cyto-kine release and hepatotoxicity. These experiments sug-gest that immunocompetent T cells play a pivotal role in concanavalin A-stimulated TNF-a release in uiuo. After intravenous administration of fluorescein isothiocya-nate-labeled concanavalin A to mice, the most fluores-cence was found within the liver. In uitro, 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 cocul-tures of these cells resulted in production of substantial amounts of TNF-a. These findings may explain the hepa-totropic effect of concanavalin A. In conclusion, T-cell-dependent concanavalin A-induced apoptotic liver in-jury in mice is related to immunological and cytokine-mediated disorders and possibly to autoreactive hepatic processes. (HEPATOLOGY 1995;21:190-198.) Abbreviations: IL,