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Role of Fas–Fas Ligand Interactions in 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD)-Induced Immunotoxicity: Increased Resistance of Thymocytes from Fas-Deficient (lpr) and Fas Ligand-Defective (gld) Mice to TCDD-Induced Toxicity

https://doi.org/10.1006/taap.1999.8753Get rights and content

Abstract

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 our laboratory demonstrated that TCDD induces apoptosis in thymocytes. In the current study, we investigated the mechanism of TCDD-induced apoptosis. Administration of a single dose of TCDD at 0.1, 1, 5, and 50 μg/kg body wt intraperitoneally, into C57BL/6 +/+ (wild-type) mice caused a dose-dependent decrease in thymic cellularity. In contrast, a similar treatment with TCDD, in Fas-deficient C57BL/6 lpr/lpr (lpr) or Fas-ligand defective C57BL/6 gld/gld (gld), mice failed to induce thymic atrophy at 0.1–5 μg/kg body wt of TCDD. In lpr and gld mice, significant thymic atrophy was seen only at 50 μg/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 of Fas+, but not Fas cells with the sera, triggered apoptosis. Also, TCDD-induced apoptosis in thymocytes was inhibited both in vitro and in vivo by caspase inhibitors. TCDD treatment caused significant up-regulation in the expression of FasL 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. Together, the current study demonstrates that Fas–Fas ligand interactions play an important role in TCDD-mediated induction of apoptosis and immunotoxicity.

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    For a long time TCDD is known to induce immune suppression, to affect the differentiation of thymic precursor T cells and to induce thymic atrophy (Fine et al., 1990; Hundeiker et al., 1999; Kremer et al., 1994; Lai et al., 1997; Laiosa et al., 2003; Lundberg et al., 1990; Lundberg, 1991; Silverstone et al., 1994). A single dose of 0.1 μg/kg BW TCDD is already effective in decreasing thymocyte numbers in mice (Kamath et al., 1999). Discussion is ongoing how TCDD induces apoptosis of thymocytes resulting in thymic atrophy.

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To whom correspondence should be addressed at the Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. E-mail: [email protected].

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