Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1

Mol Endocrinol. 2001 Jul;15(7):1062-76. doi: 10.1210/mend.15.7.0657.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Dexamethasone / pharmacology
  • Gene Expression
  • Glucocorticoids / pharmacology
  • Humans
  • Interleukin-2 / pharmacology*
  • Luciferases / genetics
  • Mammary Tumor Virus, Mouse / genetics
  • Mice
  • Mice, Inbred C3H
  • Milk Proteins*
  • Mutagenesis
  • Plasmids / genetics
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Glucocorticoid / metabolism*
  • Recombinant Proteins / pharmacology
  • STAT5 Transcription Factor
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic
  • Terminal Repeat Sequences
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transcription Factor AP-1 / physiology*
  • Transcription, Genetic* / drug effects
  • Transcriptional Activation
  • Transfection


  • DNA-Binding Proteins
  • Glucocorticoids
  • Interleukin-2
  • Milk Proteins
  • Receptors, Glucocorticoid
  • Recombinant Proteins
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • Stat5b protein, mouse
  • Trans-Activators
  • Transcription Factor AP-1
  • Dexamethasone
  • DNA
  • Luciferases