Role of Fas-Fas ligand interactions in 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)-induced immunotoxicity: Increased resistance of thymocytes from Fas-deficient (Ipr) and Fas ligand-defective (gld) mice to TCDD-induced toxicity

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental pollutant well known for its toxicity to the thymus. Recent studies from ou r laboratory demonstrated that TCDD induces apoptosis in thymocytes. In the current study, we investigated the mechanism of TCDD-induced apoptosis. Ad ministration of a single dose of TCDD at 0.1, 1, 5, and 50 mu g/kg body wt intraperitoneally, into C57BL/6 +/+ (wild-type) mice caused a dose-dependen t decrease in thymic cellularity. In contrast, a similar treatment with TCD D, in Fas-deficient C57BL/6 lpr/lpr (lpr) or Fas-ligand defective C57BL/6 g ld/gld (gld), mice failed to induce thymic atrophy at 0.1-5 mu g/kg body wt of TCDD, In lpr and gld mice, significant thymic atrophy was seen only at 50 mu g/kg body wt of TCDD. Injection of TCDD caused apoptosis only in wild -type but not in lpr or gld mice. The sera from TCDD-treated wild-type mice exhibited increased levels of soluble Fas ligand, inasmuch as incubation o f Fas(+), but not Fas(-) cells with the sera, triggered apoptosis. Also, TC DD-induced apoptosis in thymocytes was inhibited both in vitro and in vivo by caspase inhibitors. TCDD treatment caused significant up-regulation in t he expression of Fast but not Fas mRNA in the thymocytes of wild-type mice. Also, such thymocytes exhibited marked alterations in the surface markers, characteristic of cells undergoing apoptosis. In contrast, TCDD treatment caused minimal phenotypic changes in thymocytes from lpr and gld mice. Toge ther, the current study demonstrates that Fas-Fas ligand interactions play an important role in TCDD-mediated induction of apoptosis and immunotoxicit y. (C) 1999 Academic Press.