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Blood, 15 July 2005, Vol. 106, No. 2, pp. 617-625.
Prepublished online as a Blood First Edition Paper on March 31, 2005; DOI 10.1182/blood-2004-11-4390.
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Submitted November 17, 2004
Accepted March 28, 2005
Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95-ligand gene by a glucocorticoid receptor dimer
Sven Baumann, Anja Dostert, Natalia Novac, Anton Bauer, Wolfgang Schmid, Stefanie C Fas, Andreas Krueger, Thorsten Heinzel, Sabine Kirchhoff, Gunther Schutz, and Peter H Krammer*
Tumor Immunology Program, Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany
Division of Molecular Biology of the Cell I, German Cancer Research Center (DKFZ), Heidelberg, Germany
* Corresponding author; email: p.krammer{at}dkfz.de.
Glucocorticoids (GCs) play an important role in the regulation of peripheral T cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, is not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of GR to two negative glucocorticoid regulatory elements (nGRE) in the CD95 (APO-1/Fas) ligand (L)-promoter. Binding of GR to these nGREs reduces activation-induced CD95L-expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of Activation-Induced Cell Death (AICD). Thus, GC-mediated inhibition of CD95L-expression of activated T cells might contribute to the anti-inflammatory function of steroid-drugs.
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