DC-SCRIPT regulates glucocorticoid receptor function and expression of its target GILZ in dendritic cells
Abstract
Dendritic cells (DCs) play a central role in the immune system; they can induce immunity or tolerance depending on diverse factors in the DC environment. Pathogens, but also tissue damage, hormones, and vitamins, affect DC activation and maturation. In particular, glucocorticoids (GCs) are known for their immunosuppressive effect on DCs, creating tolerogenic DCs. GCs activate the type I nuclear receptor (NR) glucocorticoid receptor (GR), followed by induced expression of the transcription factor glucocorticoid-inducible leucine zipper (GILZ). GILZ has been shown to be necessary and sufficient for GC-induced tolerogenic DC generation. Recently, we have identified the DC-specific transcript (DC-SCRIPT) as an NR coregulator, suppressing type I steroid NRs estrogen receptor and progesterone receptor. In this study, we analyzed the effect of DC-SCRIPT on GR activity. We demonstrate that DC-SCRIPT coexists with GR in protein complexes and functions as a corepressor of GR-mediated transcription. Coexpression of DC-SCRIPT and GR is shown in human monocyte–derived DCs, and DC-SCRIPT knockdown enhances GR-dependent upregulation of GILZ mRNA expression in DCs. This demonstrates that DC-SCRIPT serves an important role in regulating GR function in DCs, corepressing GR-dependent upregulation of the tolerance-inducing transcription factor GILZ. These data imply that by controlling GR function and GILZ expression DC-SCRIPT is potentially involved in the balance between tolerance and immunity.
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Glucocorticoids regulate dendritic cell maturation, survival, and motility and hamper their immunogenic functions, including restricting T cell stimulation by preventing up-regulation of MHCII, B7.2, and CD40.
“In addition to regulating the maturation, survival, and motility of these antigen-presenting cells, GCs also hamper their immunogenic functions. Indeed, the end product of the HPA axis restricts the capacity of DCs to stimulate T cells by preventing the up-regulation of various co-stimulatory molecules, such as MHCII, B7.2 (CD86), and CD40 (33, 36, 37).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [37]
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The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain
Bellavance, M.-A., & Rivest, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00136 · Cited by 419 · see citing works
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- Authors
- Hontelez, S., Karthaus, N., Looman, M. W., Ansems, M., & Adema, G. J.
- Affiliations
- Radboud University Medical Center (NL)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04-01
- Volume
- 190
- Issue
- 7
- Pages
- 3172-3179
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2100261377
- Cited by
- 35
- References
- 43
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 8 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 5 · 2013: 2
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- glucocorticoid receptor, GILZ, dendritic cells, corepressors, glucocorticoid-induced immunosuppression, tolerogenic dendritic cells, monocyte-derived dendritic cells, transcriptional regulation
- MeSH terms
- Carrier Proteins, Cell Line, Cells, Cultured, Dendritic Cells, Gene Expression Regulation, Humans, Immune Tolerance, Promoter Regions, Genetic, Protein Binding, Receptors, Glucocorticoid, Transcription, Genetic, Leucine Zippers, Immunoprecipitation, Gene Knockdown Techniques, RNA Isoforms
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