M Leist1, A Wendel. 1. Faculty of Biology, University of Konstanz, Germany.
Abstract
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.
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.
Authors: K Zhu-Salzman; R E Shade; H Koiwa; R A Salzman; M Narasimhan; R A Bressan; P M Hasegawa; L L Murdock Journal: Proc Natl Acad Sci U S A Date: 1998-12-08 Impact factor: 11.205
Authors: William O Osburn; Melinda S Yates; Patrick D Dolan; Sining Chen; Karen T Liby; Michael B Sporn; Keiko Taguchi; Masayuki Yamamoto; Thomas W Kensler Journal: Toxicol Sci Date: 2008-04-15 Impact factor: 4.849