Role of death receptor pathway in estradiol-induced T-cell apoptosis in vivo
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- Role of death receptor pathway in estradiol-induced T-cell apoptosis in vivo
- Do, Yoonkyung; Ryu, SH; Nagarkatti, M; Nagarkatti, PS
- Apoptosis; Estrogen; Fas; FasL; Immunotoxicity; Thymus
- Issue Date
- OXFORD UNIV PRESS
- TOXICOLOGICAL SCIENCES, v.70, no.1, pp.63 - 72
- In the current study we investigated the mechanism by which β-estradiol-17-valerate (E2) induces apoptosis in T cells. To this end, C57BL/6 wild-type (+/+), Fas-deficient (C57BL/6-lpr/lpr), and FasL-deficient (C57BL/6-gld/gld) mice were treated with various concentrations of E2, including 75, 25, 5, 1, or 0.1 mg/kg body weight or the vehicle. The thymi from these mice were harvested on days 1, 4, or 7 following treatment, and cellularity and apoptosis were determined. Treatment with E2 caused a decrease in thymic cellularity at all doses except 0.1 mg/kg in all three groups of mice, particularly on days 4 and 7. Interestingly, however, the degree of thymic atrophy in C57BL/6-lpr/lpr and C57BL/6-gld/gld mice was significantly less than that seen in C57BL/6 wild-type mice. When thymocytes were analyzed for apoptosis, cells from C57BL/6-lpr/lpr and C57BL/6-gld/gld mice showed decreased levels of apoptosis. Moreover, cDNA array analysis of gene expression revealed that treatment with E2 upregulated several genes involved in apoptosis, including FasL, caspases, TRAIL, and iNOS, but not bcl-2 gene family. Reverse transcriptase-polymerase chain reaction data also demonstrated the increased expression of Fas and FasL genes following E2 treatment. Caspase 8 inhibitor blocked the E2-induced apoptosis of thymocytes in vitro. These data suggested that E2 may induce apoptosis by activating the death-receptor rather than the mitochondrial pathway. E2 treatment decreased the expansion of peripheral Vβ3+ T cells to the bacterial superantigen SEA in vivo and their subsequent in vitro proliferative response to SEA, thereby suggesting increased induction of apoptosis in Vβ3+ T cells. The current study suggests that E2 may trigger the death receptor pathway in vivo in T cells, thereby inducing apoptosis.
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