title: Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1.
abstract: Cytokines and glucocorticoids (GCs) signaling pathways interfere with each other in the regulation of apoptosis and gene expression in the immune system. Interleukin-2 (IL-2), through the Janus kinase/signal transducers and activators of transcription (Jak/STAT) and mitogen-activated protein kinase (MAPK) pathways, activates STAT5 and activated protein-1 (AP-1) transcription factors, respectively, which are known to repress glucocorticoid receptor (GR) activity, at least in part, through protein-protein interactions. In this work, we have analyzed the mechanisms whereby IL-2 down-regulates the GC-induced transactivation of the mouse mammary tumor virus long terminal repeat (MMTV-LTR) in murine CTLL-2 T lymphocytes. Mutagenesis studies revealed that the MMTV-LTR STAT5 binding site (-923/-914) was not required for IL-2-mediated inhibition but identified both glucocorticoid response elements (GREs) and the -104/+1 region as critical elements for this negative response. The DNA binding activities of transcription factors required for GC-mediated activation of the MMTV-LTR promoter and that bind to the -104/+1 region (nuclear factor-1, Oct-1) were not affected by IL-2 treatment. Overexpression of wild-type STAT5B enhanced the effect of IL-2 on MMTV-LTR activity, and a dominant negative form of STAT5B (Y699F) abolished the IL-2-mediated MMTV-LTR inhibition, whereas AP-1 activation had no effect in this system. Direct interaction between liganded GR and STAT5 was observed in CTLL-2 cells in a STAT5 phosphorylation-independent manner. Overexpression of nuclear coactivators CBP (CREB-binding protein) or SRC-1a (steroid receptor coactivator 1a) did not blunt IL-2 inhibitory effects. We suggest that the STAT5-repressive activity on the GC-dependent transcription may involve direct interaction of STAT5 with GR, is dependent on the promoter context and STAT5 activation level, and occurs independently of coactivators levels in T cells.
authors: INSERM U461 Faculté de Pharmacie Paris-Sud 92296 Châtenay-Malabry, France.
authors: A
authors: A
authors: Biola
authors: P
authors: P
authors: Lefebvre
authors: M
authors: M
authors: Perrin-Wolff
authors: M
authors: M
authors: Sturm
authors: J
authors: J
authors: Bertoglio
authors: M
authors: M
authors: Pallardy
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008894:Milk Proteins; D016296:Mutagenesis; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic; D020079:Terminal Repeat Sequences; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D007376:Interleukin-2; D008894:Milk Proteins; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D004247:DNA; D008156:Luciferases