DES-mediated regulation of Fas and FasL gene expression

Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-κB motifs

Key Points

  • DES Induces Alterations in Thymic Cellularity in Pregnant mice and Their Fetuses
  • DES Up-Regulates Fas and FasL Expression in Fetal Thymic Cells
  • DES Up-Regulates Fas and FasL Expression in T Cells via the ER
  • DES Regulates Fas and FasL Expression Through Their Promoters
  • DES-Induced Transcription Factors Bind with ERE and NF-κB cis-Regulatory Motifs Present in Fas or FasL Promoter

The aim of the present study was to elucidate the molecular mechanisms of DES-mediated regulation of Fas and FasL gene expression during the development of the immune system and examine the role of ERE and NF-κB motifs in the regulation of these genes.

2012 Study Abstract

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes.

To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells.

Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions.

In conclusion, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on immune cells that play a critical role in the regulation of autoimmunity and cancer. The mechanisms include DES-induced transcriptional regulation of Fas and FasL genes involving ER-mediated signaling and the participation of ERE and/or NF-κB motifs present on their promoters. Furthermore, our studies suggest that such alterations in apoptotic molecules in the thymus may affect T-cell differentiation and have long-term consequences for the immune functions.

Sources and more information
  • Full study (free access) Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs, The Journal of pharmacology and experimental therapeutics, NCBI PubMed PMC3477208, 2012 Nov.
  • Expression of Fas and FasL in fetal thymic cells after prenatal exposure to DES featured image credit PMC3477208/figure/F3.
DES DIETHYLSTILBESTROL RESOURCES

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