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Cited by 68Cytokine Signaling Pathways and InteractionsEstrogen and related hormone effectsGenomics and Chromatin Dynamics

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

Open access
Biola, A.·2001·Molecular Endocrinology
DOI 10.1210/me.15.7.1062
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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.

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  • JNK may play an important role in GR regulation under resting (unstimulated) conditions through mutually inhibitory protein-protein interactions.

    “Studies in our lab have shown that JNK may play an important role in GR regulation under resting (unstimulated) conditions through mutually inhibitory protein-protein interactions.48”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [48]

    The Introduction says GR can interact with other transcription factors, and the discussion describes mutual interference between GR and AP-1. Neither passage identifies JNK as the interacting factor or establishes GR regulation by JNK under resting conditions; the paper's own inhibitory mechanism involves IL-2 and STAT5. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Comparable effects were observed after treatment of cells with antisense oligonucleotides directed against JNK.

    “Comparable effects were observed after treatment of cells with antisense oligonucleotides directed against JNK.”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [48]

    The EMSA and DNA Affinity Precipitation methods describe oligonucleotide probes and IL-2 treatment, but not antisense oligonucleotides directed against JNK. Searches for JNK, antisense oligonucleotides, and comparable treatment effects found no passage in our copy addressing the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Changes in nuclear translocation of GR were not associated with JNK inhibition.

    “Changes in nuclear translocation of GR were not associated with JNK inhibition.”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [48]

    The discussion passage on IL-2 and GR signaling says IL-2 did not prevent GR translocation to the nucleus, but it does not assess changes in translocation in relation to JNK inhibition. Searches for “JNK” and “c-Jun N-terminal kinase” found no passage addressing that relationship. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • Pharmacologic inhibition of JNK signaling significantly increased DEX-induced GR-GRE binding, as well as DEX-induced reporter gene activity in mouse L929 fibroblasts and mouse hippocampal HT22 cells.

    “Pharmacologic inhibition of JNK signaling significantly increased DEX-induced GR-GRE binding, as well as DEX-induced reporter gene activity in mouse L929 fibroblasts and mouse hippocampal HT22 cells.”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [48]

    The Fig. 1 passage describes IL-2 effects on DEX-induced GR activity in CTLL-2 cells, and the DNA-binding methods describe recombinant rat GR. Searches for JNK inhibition, L929 cells, and HT22 cells found no passage addressing the claimed effect; the cited experiments do not establish it. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Biola, A.
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2001-07-01
Volume
15
Issue
7
Pages
1062-1076
ISSN
0888-8809 (ISSN-L)
DOI
10.1210/me.15.7.1062
OpenAlex
W2044320043
Cited by
67
References
58
Citations by year
2024: 3 · 2023: 2 · 2022: 4 · 2020: 2 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 3 · 2013: 2 · 2012: 2
FWCI
1.33
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Association pour la Recherche sur le Cancer
  • Institut National de la Santé et de la Recherche Médicale
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
interleukin-2, glucocorticoid receptor, STAT5, AP-1, glucocorticoid response element, transcriptional repression, STAT5B, transcriptional coactivator, MAPK signaling, JAK/STAT signaling
MeSH terms
Animals, Binding Sites, Cell Line, Dexamethasone, DNA, DNA-Binding Proteins, Glucocorticoids, Humans, Interleukin-2, Luciferases, Mammary Tumor Virus, Mouse, Mice, Inbred C3H, Milk Proteins, Plasmids, Promoter Regions, Genetic, Receptors, Glucocorticoid, Recombinant Proteins, T-Lymphocytes, Cytotoxic, Transcription, Genetic, Transfection, Signal Transduction, Transcriptional Activation, Trans-Activators, Gene Expression, Mutagenesis, Transcription Factor AP-1, Terminal Repeat Sequences, STAT5 Transcription Factor, Mice

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