New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation

Vandevyver, Sofie; Dejager, Lien; Tuckermann, Jan; Libert, Claude

doi:10.1210/en.2012-2045

Cited by 296Estrogen and related hormone effectsAdrenal Hormones and DisordersReceptor Mechanisms and Signaling

New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation

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Vandevyver, Sofie, Dejager, Lien, Tuckermann, Jan, Libert, Claude·2013·Endocrinology

DOI 10.1210/en.2012-2045

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Abstract

Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GR(dim/dim) mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents.

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The single point mutation A458T engineered in GRdim is unlikely to fully abrogate the formation of functional GR homodimers.
“The single point mutation A458T engineered in GRdim is thus unlikely to fully abrogate the formation of functional GR homodimers (30, 112, 113).”
From The HPA â€“ Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [30]

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Wilson (1999) · doi:10.1002/1529-0131(199907)42:7

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Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor
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Mechanisms of Action and Efficacy of Hyaluronic Acid, Corticosteroids and Platelet-Rich Plasma in the Treatment of Temporomandibular Joint Osteoarthritis—A Systematic Review
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Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age
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The Roles of Lysosomes in Inflammation and Autoimmune Diseases
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Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation
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Glucocorticoid-loaded liposomes induce a pro-resolution phenotype in human primary macrophages to support chronic wound healing
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Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD
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Toll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide
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Self-citation
A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery
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Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta
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Glucocorticoid Receptor Signaling in Diabetes
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Authors: Vandevyver, S., Dejager, L., Tuckermann, J., & Libert, C.
Affiliations: Vlaams Instituut voor Biotechnologie (BE)
Universität Ulm (DE)
Corresponding author: Libert, Claude
ORCID: Tuckermann, Jan
Libert, Claude
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2013-03-01
Volume: 154
Issue: 3
Pages: 993-1007
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2012-2045
OpenAlex: W2054115898
Cited by: 296
References: 190
Citations by year: 2026: 11 · 2025: 8 · 2024: 17 · 2023: 21 · 2022: 19 · 2021: 24 · 2020: 25 · 2019: 29 · 2018: 19 · 2017: 23 · 2016: 34 · 2015: 24 · 2014: 31 · 2013: 11
FWCI: 4.10
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
Funders: Universiteit Gent
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: glucocorticoids, glucocorticoid receptor, anti-inflammatory mechanism, receptor dimerization, transcriptional activation, transrepression, glucocorticoid response element, inflammatory diseases
MeSH terms: Animals, Anti-Inflammatory Agents, Glucocorticoids, Humans, Mice, Mutant Strains, Models, Biological, Receptors, Glucocorticoid, Signal Transduction, Transcriptional Activation, Annexin A1, Response Elements, Mice, Protein Multimerization

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New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation

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