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Role of Dioxin Response Element and Nuclear Factor-B Motifs in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Regulation of Fas and Fas Ligand Expression

Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina

We have demonstrated previously that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) up-regulates Fas and FasL in immune cells, although the molecular mechanisms remain unknown. We investigated the regulation of Fas or FasL promoter by TCDD in EL4 T cells using luciferase reporter constructs. We observed 20 ± 5- and 14 ± 4-fold induction of promoter activity for Fas and FasL, respectively, after TCDD exposure. The induction of luciferase was significantly reduced (2 ± 1-fold) in the presence of -naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist. We noted the presence of a dioxin response element (DRE) and five nuclear factor-B (NF-B) motifs on Fas promoter, and no DRE but two NF-B motifs on FasL promoter. When we investigated the role of DRE and NF-B, we observed varying levels of luciferase induction (9 ± 2-fold for DRE and 8 ± 2-fold for NF-Bs of Fas promoter and 6 ± 3-fold for NF-Bs of FasL promoter). Mutations in DRE of Fas promoter or NF-Bs of FasL promoter led to decreased luciferase induction, further supporting our results. Probes for DRE or NF-B motifs of Fas and/or FasL promoters demonstrated mobility shift in the presence of nuclear extract from TCDD-treated EL4 cells. Furthermore, we observed supershift in mobility when DRE and NF-B probes were incubated in the presence of anti-mouse AhR, and anti-NF-B (RelA/p65 and p50) antibodies, respectively. Administration of TCDD into mice caused significant increase in Fas and FasL transcripts in thymus and liver. These data demonstrate that TCDD regulates Fas and FasL promoters through DRE and/or NF-B motifs via AhR.

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