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New Insights into the Anti-inflammatory Mechanisms of Glucocorticoids: An Emerging Role for Glucocorticoid-Receptor-Mediated Transactivation
Open accessAbstract
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 thus unlikely to fully abrogate the formation of functional GR homodimers (30, 112, 113).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [30]
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“…the dimerized GC/GR complex is also capable of binding to positive GREs and thereby up-regulating the expression of multiple genes, many of which are related to the metabolic adverse effects of GCs (Rhen and Cidlowski, 2005; Clark and Belvisi, 2012; Nixon et al., 2013; Vandevyver et al., 2013).”
BackgroundGlucocorticoid signaling and osteoarthritis.
Savvidou, O., Milonaki, M., Goumenos, S., Flevas, D., Papagelopoulos, P., & Moutsatsou, P. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.11.001 · Cited by 41
The long winding road to the safer glucocorticoid receptor (GR) targeting therapies
Lesovaya, E. A., Chudakova, D. A., Baida, G. E., Михайловна, Ж. Е., Игоревич, К. К., Геннадиевна, Я. М., & Budunova, I. V. (2022) · Oncotarget · doi:10.18632/oncotarget.28191 · Cited by 43
Prodrug Approach as a Strategy to Enhance Drug Permeability
de Souza, M. M., Gini, A. L. R., Moura, J. A., Scarim, C. B., Chin, C. M., & dos Santos, J. L. (2025) · Pharmaceuticals · doi:10.3390/ph18030297 · Cited by 47
“Consequently, inflammation and immune response due to inflammation, the causative factors of psoriasis, are reduced [165].”
Rollins, D. A., Kharlyngdoh, J. B., Coppo, M., Tharmalingam, B., Mimouna, S., Guo, Z., Sacta, M. A., Pufall, M. A., Fisher, R. P., Hu, X., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01569-2 · Cited by 44
PI3K inhibitors protect against glucocorticoid-induced skin atrophy
Agarwal, S., Mirzoeva, S., Readhead, B., Dudley, J. T., & Budunova, I. V. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.01.055 · Cited by 42
González, F. B., Villar, S. R., Bussy, R. F., Martin, G. H., Pérol, L., Manarin, R., Spinelli, S. V., Pilon, C., Cohen, J. L., Bottasso, O. A., et al. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.11.016 · Cited by 41
“Is known that glucocorticoids mediate their biological effects through the binding to their cognate intracellular receptor, which translocates to the nucleus and targets specific sequences called glucocorticoid response elements (GREs) in the promoter regions of glucocorticoid-inducible genes (Vandevyver et al., 2013).”
van den Heuvel, J. K., Boon, M. R., van Hengel, I. A. J., der Put, E. P., van Beek, L., van Harmelen, V., van Dijk, K. W., Pereira, A. M., Hunt, H., Belanoff, J. K., et al. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13477 · Cited by 42
“Previous studies primarily aiming at potent anti-inflammatory efficacy showed potential for these so-called dissociated compounds or selective GR modulators (e.g. De Bosscher et al., 2010; Vandevyver et al., 2013); however, the potential beneficial effects for diet-induced obesity have not yet been explored.”
BackgroundNew Immunosuppressive Therapies in Uveitis Treatment
Mérida, S., Palacios, E., Návea, A., & Bosch‐Morell, F. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160818778 · Cited by 41
“However some recent studies, which used mutant mice in which the glucocorticoid receptor was mostly dimerization defective due to the replacement of an alanine with a threonine, have shown that glucocorticoid receptor dimers also account for resolving inflammation [21].”
BackgroundThe Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions
Vasconcelos, A. R., Cabral‐Costa, J. V., Mazucanti, C. H., Scavone, C., & Kawamoto, E. M. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00009 · Cited by 41
GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life
Louw, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01693 · Cited by 42
“Despite the fact that the usefulness of this paradigm has been challenged as being outdated and oversimplifying the complexity of GR-signaling by negating the role of GR dimers in curbing inflammation and the role of GR monomers in eliciting side-effects (19, 22), it may still hold promise for drugs tailored to specif…”
BackgroundAir pollution and resistance to inhaled glucocorticoids: Evidence, mechanisms and gaps to fill
Rider, C. F., & Carlsten, C. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.005 · Cited by 40
Boix, J., Sevilla, L. M., Sáez, Z., Carceller, E., & Pérez, P. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.07.018 · Cited by 42
“INTRODUCTION The mineralocorticoid receptor (MR) and glucocorticoid (GC) receptor (GR) are structurally and functionally related proteins that belong to the steroid receptor superfamily and act as ligand-activated transcription factors recognizing the same hormone responsive elements on target genes (Oakley and Cidlow…”
BackgroundThe Management of Glucocorticoid Therapy in Liver Failure
Xue, R., & Meng, Q. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02490 · Cited by 37
Wong, C.-Y., Bezhaeva, T., Rothuizen, T. C., Metselaar, J. M., de Vries, M. R., Verbeek, F. P. R., Vahrmeijer, A. L., Wezel, A., van Zonneveld, A. J., Rabelink, T. J., et al. (2016) · Scientific Reports · doi:10.1038/srep30439 · Cited by 35
Noise-induced cochlear inflammation
Tan, W. J. T. (2013) · World Journal of Otorhinolaryngology · doi:10.5319/wjo.v3.i3.89 · Cited by 34
Relationship Between Glucocorticoids and Insulin Resistance in Healthy Individuals
Zhou, P.-Z., Zhu, Y., Zou, G.-H., Sun, Y., Xiu, X., Huang, X. Y., & Zhang, Q. (2016) · Medical Science Monitor · doi:10.12659/msm.895251 · Cited by 35
“GCs exert their functions through binding to their intracellular receptor, known as the glucocorticoid receptor (GR), which is a ligandinducible transcription factor that belongs to the nuclear receptor superfamily [5].”
BackgroundYang, Z.-G., Lei, X., & Li, X. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4154 · Cited by 35
“Although glucocorticoids have a powerful capability in suppressing the inflammatory process (8,9), this effect is correlated with the magnitude and duration of inflammation (7,10,11).”
Lesovaya, E. A., Agarwal, S., Readhead, B., Vinokour, E. I., Baida, G. E., Bhalla, P., Игоревич, К. К., Геннадиевна, Я. М., Platanias, L. C., Dudley, J. T., et al. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.02.045 · Cited by 35
“GR nuclear import and transactivation function strongly depend on GR phosphorylation (Lesovaya et al., 2015; Vandevyver et al., 2013), which is mediated by MAPKs, CDKs, and GSK-3β (Chen et al.”
BackgroundDexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity
Melnik, D., Sahana, J., Corydon, T. J., Kopp, S., Nassef, M. Z., Wehland, M., Infanger, M., Grimm, D. G., & Krüger, M. (2020) · Cells · doi:10.3390/cells9020367 · Cited by 35
“pharmacodynamic effects through binding to glucocorticoid receptors (GRs) [2], which interact downstream with signaling molecules in the cytoplasm or are able to translocate into the nucleus, where they repress the activity of other transcription factors (such as nuclear factor kappa-lightchain-enhancer of activated B…”
BackgroundDimerization of glucocorticoid receptors and its role in inflammation and immune responses
Yang, M., Chen, J., & Wei, W. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105334 · Cited by 35
Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis
Sevilla, L. M., & Pérez, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02220 · Cited by 33
“GR induces genes encoding for anti-inflammatory mediators such as GC-Induced-Leucine-Zipper (GILZ), Dual-Specificity protein Phosphatase 1 (DUSP1), Inhibitor of kappaB alpha (IκBα), and Zinc Finger Protein 36/TrisTetraProlin (ZFP36/TTP) (6).”
BackgroundTranscriptional glucocorticoid effects in the brain: Finding the relevant target genes
Meijer, O. C., Buurstede, J. C., Viho, E. M. G., Amaya, J. M., Koning, A.-S. C. A. M., van der Meulen, M., van Weert, L. T. C. M., Paul, S. N., Kroon, J., & Koorneef, L. L. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13213 · Cited by 34
“This mechanism received much attention because of its promise to clinically separate anti-inflammatory effects from the side effects of such therapies.(50) However, this concept recently met with criticism because new approaches suggest that some form of direct DNA binding is occurring in all instances, and that previ…”
BackgroundHu, Y., Wang, D., Zhai, K., & Tong, Z. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2015-0356oc · Cited by 31
“The binding of GC/cGR induces both increased expression of antiinflammatory molecules as well as decreased expression of proinflammatory genes (5, 6).”
Takeshita, Y., Watanabe, S., Hattori, T., Nagasawa, K., Matsuura, N., Takahashi, K., Murohara, T., & Nagata, K. (2015) · Hypertension Research · doi:10.1038/hr.2015.77 · Cited by 32
Ayyar, V. S., Almon, R. R., Jusko, W. J., & DuBois, D. C. (2015) · Physiological Reports · doi:10.14814/phy2.12382 · Cited by 34
“However, this view has been challenged in recent years (Newton and Holden 2007; Vandevyver et al. 2013).”
BackgroundPetrillo, M. G., Fettucciari, K., Montuschi, P., Ronchetti, S., Cari, L., Migliorati, G., Mazzon, E., Bereshchenko, O., Bruscoli, S., Nocentini, G., et al. (2014) · BMC Pharmacology and Toxicology · doi:10.1186/2050-6511-15-35 · Cited by 31
“These compounds can also inhibit lymphocyte proliferation and induce lymphocyte death [1-3].”
Background
Metadata
- Authors
- Vandevyver, S., Dejager, L., Tuckermann, J., & Libert, C.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Universität Ulm (DE)
- Corresponding author
- 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
- 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 › Endocrinology › 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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