TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS DURING THE POISONING OF MICE WITH HEPATOTOXINS

Background & Aims: Treatment with tumor necrosis factor (TNF) induces murine hepatocyte apoptosis in vitro and in vivo when sensitizing conc entrations of toxins are present. The aim of this study was to investi gate whether endogenously formed INF contributes to liver failure caus ed by hepatotoxins. Methods: The extent of liver damage, induced by cc -amanitin or actinomycin D (ActD), was examined under various experime ntal conditions, preventing the action of TNF on hepatocytes. Results: TNF induced apoptosis of murine hepatocytes or human hepatoma cells i n the presence of alpha-amanitin or ActD. TNF and alpha-amanitin induc ed such hepatotoxicity also in vivo in a synergistic way. After in viv o administration of high doses of ActD or alpha-amanitin alone, hepati c TNF-messenger RNA was increased and hepatocytes underwent apoptosis. A neutralizing antiserum against TNF-alpha prevented the liver injury . Hepatotoxicity of ActD or alpha-amanitin also was prevented by pretr eatment of mice with low doses of the tolerizing cytokine interleukin 1. Mice deficient for the 55-kilodalton-TNF receptor were protected fr om ActD- or alpha-amanitin-induced toxicity. Endotoxin-unresponsive C3 H/HeJ mice also had liver failure after ActD treatment, and this damag e was prevented by treatment with anti-TNF antiserum. Conclusions: Hep atotoxins such as alpha-amanitin may induce liver failure by an indire ct mechanism involving sensitization of parenchymal cells toward endog enously produced TNF.