A novel mechanism of murine hepatocyte death inducible by Concanavalin A

Background: Concanavalin A (Con A) is a plant lectin that polyclonally activates T-cells. When given intravenously to mice it induces a selective liver failure. Hepatotoxicity following Con A administration involves the systemic release of tumor necrosis factor. Methods: We used primary murine hepatocyte cultures to investigate mechanisms of hepatocytotoxicity related to this animal model of inflammatory liver failure. Results: Con A was directly toxic for cultured hepatocytes. This toxicity did not require additional cytokines or the presence of T cells. Cytotoxicity due to Con A involved specific binding of the lectin to mannosyl cell surface receptors, but no internalization. Other structurally similar lectins lacked such an in vitro hepatocytotoxicity. Con A induced initially reversible alterations of the morphology that were different from the ones caused by classical hepatotoxins. Con A-induced cell death was highly specific for murine hepatocytes. It was neither apoptotic by morphology nor did it involve DNA fragmentation. In addition, Con A caused a fall in cellular total glutathione content and an increase in transcriptional activity. Stabilization of microtubules by taxol completely protected cells from the lectin. Conclusions: Stimulation of hepatocytes with Con A elicits a novel mechanism of cytotoxicity due to inappropriate excessive stimulation of membrane receptors and subsequent disturbance of the cytoskeleton.