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Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions

Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions

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SCHWADERER, Juliane, Ann-Kathrin GAISER, Truong San PHAN, M. Eugenia DELGADO, Thomas BRUNNER, 2017. Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions. In: Cell Death & Disease. 8, e2745. eISSN 2041-4889. Available under: doi: 10.1038/cddis.2017.173

@article{Schwaderer2017-04-13Liver-39324, title={Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions}, year={2017}, doi={10.1038/cddis.2017.173}, volume={8}, journal={Cell Death & Disease}, author={Schwaderer, Juliane and Gaiser, Ann-Kathrin and Phan, Truong San and Delgado, M. Eugenia and Brunner, Thomas}, note={Article Number: e2745} }

Gaiser, Ann-Kathrin Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions Delgado, M. Eugenia Delgado, M. Eugenia 2017-04-13 Schwaderer, Juliane Brunner, Thomas 2017-06-20T08:31:32Z eng CD95/Fas ligand (FasL) is a cell death-promoting member of the tumor necrosis factor family with important functions in the regulation of T-cell homeostasis and cytotoxicity. In T cells, FasL expression is tightly regulated on a transcriptional level involving a complex set of different transcription factors. The orphan nuclear receptor liver receptor homolog-1 (LRH-1/NR5a2) is involved in the regulation of development, lipid metabolism and proliferation and is predominantly expressed in epithelial tissues. However, its expression in T lymphocytes has never been reported so far. Based on in silico analysis, we identified potential LRH-1 binding sites within the FASLG promoter. Here, we report that LRH-1 is expressed in primary and secondary lymphatic tissues, as well as in CD4<sup>+</sup> and CD8<sup>+</sup> T cells. LRH-1 directly binds to its binding sites in the FASLG promoter, and thereby drives FASLG promoter activity. Mutations in the LRH-1 binding sites reduce FASLG promoter activity. Pharmacological inhibition of LRH-1 decreases activation-induced FasL mRNA expression, as well as FasL-mediated activation-induced T-cell apoptosis and T-cell cytotoxicity. In a mouse model of Concanavalin A-induced and FasL-mediated hepatitis pharmacological inhibition of LRH-1 resulted in decreased hepatic FasL expression and a significant reduction of liver damage. In summary, these data show for the first time LRH-1 expression in T cells, its role in FASLG transcription and the potential of pharmacological inhibition of LRH-1 in the treatment of FasL-mediated immunopathologies. Gaiser, Ann-Kathrin Brunner, Thomas Schwaderer, Juliane Phan, Truong San 2017-06-20T08:31:32Z Phan, Truong San

Dateiabrufe seit 20.06.2017 (Informationen über die Zugriffsstatistik)

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