Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer.
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, are 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 the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs 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.
Baumann
Sven
S
Tumor Immunology Program, Division of Immunogenetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Dostert
Anja
A
Novac
Natalia
N
Bauer
Anton
A
Schmid
Wolfgang
W
Fas
Stefanie C
SC
Krueger
Andreas
A
Heinzel
Thorsten
T
Kirchhoff
Sabine
S
Schütz
Günther
G
Krammer
Peter H
PH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D019281:Dimerization; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D011965:Receptors, Glucocorticoid; D019014:fas Receptor; D003907:Dexamethasone; D004247:DNA; D003513:Cycloheximide