Next Article in Journal
Computational Neuroscience’s Influence on Autism Neuro-Transmission Research: Mapping Serotonin, Dopamine, GABA, and Glutamate
Previous Article in Journal
PLpro Inhibitors as a Potential Treatment for COVID-19
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 13
Issue 6
10.3390/biomedicines13061418
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Glucocorticoid Insensitivity: Is It a Question of Time and Place?

by
Christopher Lambers
1,* and
Michael Roth
2
1
Department Pneumology, Ordensklinikum Linz Elisabethinen, AT-4020 Linz, Austria
2
Pulmonary Cell Research, Department of Biomedicine & Clinic of Pneumology, University and University Hospital Basel, CH-4031 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Biomedicines 2025, 13(6), 1418; https://doi.org/10.3390/biomedicines13061418
Submission received: 5 May 2025 / Revised: 5 June 2025 / Accepted: 7 June 2025 / Published: 10 June 2025
(This article belongs to the Special Issue Unraveling the Role of Glucocorticoid Receptor in Inflammation and Cancer)
Browse Figures
Versions Notes

Abstract

Background: Glucocorticoid insensitivity is a problem for the therapy of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Both are non-communicable chronic inflammatory lung diseases with worldwide increasing incidences. Only symptoms can be controlled by inhaled or systemic glucocorticoids, often combined with β2 agonists and/or muscarinic receptor antagonists. The therapeutic effect of glucocorticoids varies between individuals, and a significant number of patients do not respond well. It is believed that only protein-free circulating unbound glucocorticoids can enter cells by diffusion and achieve their therapeutic effect by binding to the intracellular glucocorticoid receptor (GR), encoded by the NR3C1 gene, for which over 3000 single-nucleotide polymorphisms have been described. In addition, various GR protein isoforms result from 11 transcription start sites, and differential mRNA splicing leads to further GR protein variants; each can be modified post-translational and alter steroid response. To add more variety, some GR isoforms are expressed cell-type specific or in a sub-cellular location. The GR only functions when it forms a complex with other intracellular proteins that regulate ligand binding, cytosol-to-nuclear transport, and nuclear and cytosolic action. Importantly, the timing of the GR activity can be cell type, time, and condition specific. These factors are rarely considered when assessing disease-specific loss or reduced GR response. Conclusions: Future studies should analyze the timing of the availability, activity, and interaction of all components of the glucocorticoid signaling cascade(s) and compare these factors between non-diseased and diseased probands, applying the combination of all omics methods (250).

1. Introduction

According to the 2024 GINA report, 300 million people currently suffer from asthma worldwide, causing approximately 1000 deaths per day [1]. The yearly incidence of asthma is increasing worldwide but varies when comparing different countries for many reasons, such as the lack of clear diagnostic tests, the wide variation of symptoms, overlapping symptoms with other lung diseases, and the lack of national registers in most countries [1,2]. As an example, the American Lung Association reported that between 1999 and 2023, the incidence of asthma increased by 19.1% in the USA [2]. Not only are the patients affected but the disease results in a major loss of school attendance and working hours, and it contributes to increasing health care costs and reduced quality of life for the patients. Importantly, in the wake of the COVID-19 pandemic, the incidence of chronic inflammatory lung diseases seems to increase worldwide [3].
The prevalence of chronic obstructive pulmonary disease (COPD) was estimated to have affected 392 million patients in 2019 [4]. The major risk factors for COPD were listed as male sex, smoking, and a low body mass index, as well as exposure to biomass, dust, or smoke in the environment or workplace. COPD cannot be cured; only its progress can be slowed [4,5,6].
For both diseases, asthma and COPD, glucocorticoids are often prescribed for life, with the aim of controlling inflammation. However, the response to glucocorticoids varies among patients, and this individual response, including insensitivity, cannot be predicted [5,6]. Both diseases are assumed to involve poly-genetic predispositions, which are not well understood [7]. A frequent reason for asthma might be seen in the wide variation of the genetic and post-translational modifications of the glucocorticoid receptor (GR), as we will show later. Glucocorticoids have been used for 80 years to treat inflammatory diseases, and their mode of action has been studied in detail. However, there is no method to determine or predict an individual’s steroid response prior to treatment [8]. The individual differences regarding the sensitivity to steroids are important to the beneficial as well as to the unwanted side effects of the drugs [9]. Steroid sensitivity can be modified by daytime, seasons, sex, and/or age [10,11]. Reduced or missing response to glucocorticoids was reported in nearly 30% of patients diagnosed with autoimmunity, inflammation, or malignancies [11]. In clinics, individual steroid sensitivity can present as increased side effects, reduced anti-inflammatory efficacy that limits disease control, or unaffected disease progression [12].
Moreover, the timing of GR availability can be modified by steroids and environmental conditions and thus cause temporary or lasting reduced steroid sensitivity [13,14]. Such effects have been reported for several steroids, alone or in combination with other medications, thereby modifying the patient’s response to therapy [15]. Furthermore, the transcriptional activity of the GR in response to steroids can be cell-type specific and time dependent in isolated primary cells [16,17]. However, investigations to determine, e.g., the disease-specific timing of these mechanisms, are missing.

2. The Glucocorticoid Receptor

The major therapeutic action of glucocorticoids is their anti-inflammatory effect, which was thought to mainly occur through their function as an intracellular transcription factor [18,19]. However, this mode of action of the GR is too simplistic. The unligated inactive GR is present in the cytosol, forming a complex with heat shock proteins (HSPs), including HSP40, HSP70, and HSP90, together with HDAC5 [20,21,22]. Upon phosphorylation, HSP40 and HSP70 dissociate from the complex and make space for FK506-binding protein 5 (FKBP51), which enables glucocorticoid binding [20]. Upon the binding of a glucocorticoid, FKBP51 is exchanged for FKBP52, which allows HSP90 to bind with dynein, leading to active transport of the GR into the nucleus (Figure 1). The strength of the interaction between the GR and FKBP51 depends on the corresponding gene alleles and feedback regulation through steroids [23,24]. The latter represents a negative feedback loop to control steroid sensitivity, which might be enhanced in patients with steroid insensitivity [24].
In the nucleus, the GR either acts as a monomer or forms a dimer with a second ligated GR. Both GR forms recognize and bind to a specific DNA sequence, named the glucocorticoid response element (GRE), which is part of many promoters of pro-inflammatory protein-encoding genes, and it down-regulates their expression [20] (Figure 1). The nuclear action of the GR has been summarized by many others and, therefore, this review will not describe the details [8,12,20,23].
The GR is encoded by the NR3C1 gene, which consists of nine exons [25]. Exon 1 contains 11 untranslated promoter variants, which can affect the transcription of the mRNAs [20]. Exons 2–9 encode the GR mRNA, which can result in at least five different mRNAs with corresponding different GR proteins [20]. Furthermore, the translation of some GR mRNAs has been reported to vary due to different translation start sites, which might be related to cell type or disease-specific translation of the GR mRNA. Overall, more than 3000 single-nucleotide polymorphisms (SNPs) of the NR3C1 gene have been reported, but the knowledge of their function or biological activity is limited [26]. Most of the NR3C1 SNPs were located in exons, which might affect the structure of the encoding DNA region and, therefore, the binding affinity of the transcription machinery, as has been described for other hormone-encoding genes [27]. Thus, some NR3C1 gene SNPs might alter the protein sensitivity to steroids in a specific individual, but even larger clinical studies on the most common NR3C1 gene SNPs are missing. Some studies discussed the possibility that NR3C1 gene SNPs have an exclusive tissue or cell-type specific effect, but these observations were mainly made in animal models, and it is an ongoing matter of debate how far animal models of the GR represent human physiology or pathophysiology [28,29,30].

3. The Regulation of GR Function by Time

It is well known that the effects of steroids and the function of the GR underlie a circadian control mechanism, which depends on the presence of co-regulating proteins, such as FKBP51 [31]. In addition, FKBP51 overexpression affects the circadian effect of the GR [32]. The function of the GR is also modified by circadian regulators, such as melatonin [33]. Other than in lung cells, GR activity was modulated by a circadian-regulated basement membrane structure, which might be an important factor for steroid transportation across the cell membrane and which has to be investigated in other cell types and in regard to disease specificity [34]. Vice versa, steroids can also control the circadian rhythm of cells, e.g., in the testicles, heart, fibroblasts, etc. [35,36,37]. Asthma and COPD studies on the circadian rhythm of GR activity are lacking, even though they were indicated by several investigations [38,39] (Figure 1).
Only for asthma did a few studies report the effect of the circadian rhythm on the availability and function of the GR. Over 25 years ago, evidence was presented that the binding capacity and signaling of the GR is reduced in patients with nocturnal asthma, but hardly any study followed up to gain more details of this condition [39,40]. The same investigators presented a similar link between the circadian rhythm of GR function and steroid insensitivity in macrophages [41]. In turn, asthma medications, including steroids and β2 agonists, can modify the circadian rhythm and thereby alter the drug’s efficacy in vitro and in vivo [42]. In mice, the optimization of drug application in line with the circadian rhythm showed improved response [43]. In human epithelial cells, the circadian rhythm was decisive for their response to steroids via the GR [44]. However, such precise timing of medication will require strict co-operation of the patients.
Referring to the different GR isoforms that can be derived from the NR3C1 gene, some alleles have been reported to affect the circadian response to steroids [10]. Moreover, both the innate and the adaptive immune response are controlled by a circadian rhythm through the action of the GR [45]. It remains unclear if these findings, which were mainly obtained in isolated cells or animal models, can be translated 1:1 to humans [46]. It should also be investigated if all GR isoforms interact in the same way with those regulatory and transporting proteins that have been described for the function of GRα. Do all GR isoforms undergo control via the circadian rhythm? Only a few of the NR3C1 gene alleles have been assessed for functional differences, and these studies are mainly based on theoretical changes of function based on protein modeling.

4. The Chromatin Structure Regulates Steroid Response

The chromatin, which regulates the access of transcription-regulating proteins, such as the GR, to the DNA, does not have a fixed structure and undergoes continuous conformational changes. These structural changes of the chromatin can be affected by the microenvironment of cells or organisms, including the composition of the extracellular matrix, the presence of inflammatory cells, cigarette smoking, exposure to chemicals, etc., as well as by other conditions, such as pregnancy, diseases, or medication [47,48,49,50].
Interestingly, exposure to some of the risk factors for chronic inflammatory diseases during the embryonic stage is indicated to pre-set the development of asthma or COPD during adult life [49,50,51,52,53,54]. Another important factor that can modify the function of steroids is the location of the GRE in the context of other transcription factor binding sites. It was implicated that the position of the GRE within the three-dimensional structure of the local chromatin affects the transcriptional efficacy of the GR [51]. The GR’s binding strength to a specific GRE is affected by the location of this GRE within the structure of the chromatin or by the distance to other transcription factor binding sites [52,53,54]. At least in vitro, the effects of the GR can be memorized over some time in primed cells by an unknown mechanism, and this might explain partly how reduced or enhanced steroid sensitivity is handed down over generations [55,56,57,58,59]. The reason why some conditions, such as modified chromatin structures, are inherited or not remains to be discovered [57,58,59,60]. Some data suggested that the timing of the priming event might be important, but the precise mechanism remains elusive, and it is unclear whether such events are reversible in the next generations (Figure 2).
The changes of the chromatin and, therefore, the GRE are regulated by the phosphorylation, sumoilation, ubiquitinilation, etc., of histones as well as transcription factors. The effects of these protein structural and functional changes depend on the timing of each event [61,62]. The interaction between the GR and the chromatin structure of its target genes had been summarized by Lovem et al., and it was concluded that there are many gaps of knowledge to be filled before we will be able to understand these mechanisms, which might be target gene specific [63]. Furthermore, the binding of the GR to the GRE might alter the structure of the chromatin in a broader area and affect its own binding capacity and the transcription of neighboring genes, probably in a cell-type or tissue-specific manner [64,65,66]. This ongoing change in the chromatin structure alters the position of transcription factor binding sites to each other, including that of the GRE and, thus might modify its interaction or accessibility to the GR, leading to altered steroid sensitivity [64,65,66].
Some data suggest that the cell-type specific regulation of steroid-regulated genes is defined by the structure of the chromatin, as was indicated in other diseases [62,67,68]. None of these changes of the local chromatin structure that regulate the access of the GR to the GRE or other transcription factor binding sites have been analyzed regarding the kinetic of steroid response in a disease-specific manner. Nevertheless, the available data indicates that small changes in these regulatory mechanisms might cause tissue structural changes, and they can also alter the sensitivity to steroids and, therefore, they need to be investigated.
Another problem in conducting such investigations might be the uncertain definition of chronic inflammatory lung disease stages [69,70,71,72,73]. Small changes in the kinetics of such protein modifications can affect the function of cells and the response to hormones and medication. Theoretically, such changes in the kinetic of any protein that is involved in the GR structure/function regulation can lead to reduced or increased steroid response, and corresponding studies should be conducted.

5. GR Isoforms: Their Origin and Regulation

The impaired function of the GR has been explained by modified DNA sequences of the encoding NR3C1gene, and several NR3C1 alleles have been linked to reduced steroid response; however, many steroid-insensitive patients do not carry such a mutation [74,75]. Some of the NR3C1 alleles cause alternative transcription start sites, which resulted in five different mRNAs and corresponding GR proteins [20,75,76,77] (GRα, GRβ GRγ GR-A, GR-P). In asthma alone, a further 21 GR isoforms have been described [76], but it remains unclear when and why the different GR isoforms occur. There is even less information about the functional consequences of these GR isoforms. One report suggested that different GR isoforms occur in a tissue or cell-type specific pattern and exert distinct transcriptional activity [77].
There are more variations of the GR protein resulting from alternative translation; at least for GRα, seven such variants have been described (GRα-B, -C+, C2, C3, D1, -D2, -D3) [20,78]. Importantly, the regulation of the expression of these different GR protein isoforms is not well understood but is certainly not based on known genetic alterations. The action of the GR on inflammation and remodeling depends on its interaction with the GRE and other transcription factors, as well as with their binding sites on different target genes [78,79]. Taking into account that we do not understand the role of chromatin formation in time and location; it is possible that genetic alterations of certain DNA sequences might play a regulatory role and thus impact steroid sensitivity [80,81,82].
Some studies implied that the expression of these GR isoforms is regulated by condition, cell type, or circadian rhythm [83,84]. It remains to be studied if the regulation and function of these GR isoforms are linked to specific conditions or kinetics. Most studies suggested that the transcriptional function of GRα is hindered by competitive GRE binding through other GR isoforms [85,86,87].
Specific splicing of GR mRNA to form GRβ can be directed by other hormones, such as dehydroepiandrosterone [86]. There is evidence that the transcription of GR splicing variants changes during development and thus, steroid sensitivity might change from juvenile to adult life [88]. GRγ shares 94% homology with GRα and has an additional amino acid within the DNA binding site [86]. GR-A lacks exons 5–7 and, therefore, its ligand binding is reduced; it has been described to be expressed higher in some areas of the cortex when compared to GRα [87]. This finding implies that studies should be conducted on age-dependent GR expression by application of transcriptomic analyses. In an animal model, the splicing isoform, GR-P, has been reported to modify the function of GRα in a cell-type specific manner using [89,90]. In humans, the expression of GR-P occurred mainly in the placenta and was altered by maternal and embryonic conditions [89,90,91].
Furthermore, 21 GR isoforms have been described in the lymphocytes of healthy probands and asthma patients, but their link to steroid responsiveness is unknown [78]. Other data implied a sub-cellular specific distribution and function of GR isoforms and, therefore, an organelle-specific steroid response. GRγ has been associated with steroid effects on mitochondria activation and modified cellular energy levels [92]. Children with acute lymphoblastic leukemia showed reduced clinical steroid response, and in isolated cells, steroids up-regulated GR-γ expression over 10 h, while it returned to baseline expression afterwards in probands with normal clinical response [93]. In the same patient group, it was shown that the GRγ-isoform had approximately 50% GRα activity and was assumed to be the cause of reduced steroid response [94]. Assuming that the transcription and translation of any GR isoform is delayed or advanced compared to GRα, this will affect the availability and function of the GR signaling cascade in a disease or cell-type specific manner, but such studies are missing [95].
Furthermore, GRα alone can be modified at the post-translational level into seven different structures, mainly affecting the N-terminal domain. Moreover, the structure and function of the GR can be altered post-translationally by phosphorylation, sumoilation, and/or ubiquitinilation [95,96,97]. The modification of different phosphorylation sites within the GR protein led to distinct activities regarding the target promoter, but the kinetic of these modifications has not been well studied [89]. Regarding the distinct GR isoforms, mainly the role and modification of the GRβ isoform but not that of the other isoforms have been investigated regarding steroid insensitivity in the context of cell-type specific and kinetic activity [97,98]. Referring to the above-named GR isoforms resulting from either different transcription start sites, mRNA splicing or post-transcriptional modifications would be of interest in assessing whether their expression follows a circadian rhythm (Figure 3).

6. GR Interaction and Regulation by Other Transcription Factors

Alternatively, or in addition to the above-described direct action as a transcription factor, the GR forms a complex with another transcription factor, which modifies the binding of these to their specific GRE DNA sequences [20]. For example, a single ligated GR inhibits the transcription-inducing effect of pro-inflammatory transcription factors by forming a complex with them, e.g., NFkB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells), AP-1 (activator protein-1), C/EBPs (CCAAT enhancer-binding proteins), or CREBP (cyclic AMP-binding protein) [99,100,101,102,103]. The GR can bind other free transcription factors or those that are already bound to their specific DNA sequence and thereby lower inflammation [21,22,23]. This complex formation can occur in either the cytoplasm or in the nucleus [21,22,23]. However, the precise mechanism by which the GR limits the action of other transcription factors, especially of those already bound to their promoter sequence, is unknown for most and could result from steric hindrance blocking the access of the transcription machinery or affecting the three-dimensional structure of the surrounding chromatin [104,105,106]. It can be speculated that such events are disease specific and alter steroid response.
The GR also controls cell proliferation, which contributes to the limitation of cell growth and is important to tissue remodeling in asthma. In isolated airway smooth muscle cells of healthy probands, the synchronization of GRα and C/EBP-α activity was achieved by the combination of steroids with β2 agonists, resulting in enhanced production of the anti-proliferative protein p21 (Waf1/Cip1) [107]. In human lung macrophages and epithelial cells, a similar effect of β2 agonists was observed after inhalation of the drug alone or with steroids, which reduced the activation of pro-inflammatory signaling pathways [108,109,110,111,112]. However, in airway smooth muscle cells of asthma patients, the anti-proliferative effect of combined drugs was not observed, while the anti-inflammatory effect occurred at a slower path compared to healthy controls [113]. Furthermore, the timing of the GRα—C/EBP-α interaction might be affected by infection, cell environment, or inflammatory conditions [108,109,110,111,112,113].
Moreover, the GRα can be activated by β2 agonists or the mineralocorticoid receptor, independent of ligation, and this alters the timing of its activity [114,115]. Other factors, such as cell density, circadian rhythm, and nutrition status, might affect the action of the GR, as had been implied by in vitro experiments in human primary cells [111,116]. Most GR ligands induced a fast translocation into the nucleus within 15–30 min [117], but some have been reported to need more time due to an unknown hindering mechanism [111,112,113,118]. Thus, it remains to be investigated if the kinetic of these interaction diseases specifically regulates the active phase of the GR and its complex formation with co-transcription factors, as was suggested by in vitro data [118,119,120].
Reduced steroid sensitivity correlated with the severity of asthma [121] and with a history of smoking [122]. Regarding tissue remodeling, mechanical stress, and the resulting reduced efficacy of steroids in COPD patients, the timely interaction with other proteins might be important and remains to be studied at different disease stages [123,124]. By which mechanism COPD patients can acquire reduced steroid sensitivity in lung immune cells and circulation lymphocytes remains unclear and might even vary between patients [7,11]. Reduced immune response by the GR can be acquired during the cause of COPD through either interacting the GR with Th2 high-inflammatory signature (TAC1) proteins or by regulating its expression; thus, it is difficult to say which event is first [24]. Furthermore, the effect of steroids on TAC1 regulation by the GR depends on the promotor structure of the TAC1 gene [125].

7. Steroid Availability and Its Regulation

Despite the above-described structural alterations of the GR protein, other mechanisms can affect the timely availability of steroids. It is assumed that only freely circulating steroids can penetrate the cell wall and exert their intracellular action [126,127]. Circulating steroids are bound corticosteroid-binding globulin (CBG), but the regulatory mechanism underlying the balance of CBG-bound and free steroids is not well understood and has not been reinvestigated in recent years [128,129]. Genetic variants of CBG have been described, but their effect on the ratio of free and bound steroids is not well determined [130] and is affected by the presence of pro-inflammatory cytokines, such as interleukine-6 [131]. However, the details and timing of these regulatory processes remain unknown.
In the context of steroid insensitivity, it has to be noted that inflammatory conditions reduce CBG fast and result in increased levels of free steroids [132]. It was reported that different synthetic steroids bind with different strengths to CBG and are also released in a drug-specific pattern [130], but whether these differences are linked to steroid insensitivity remains to be studied. Furthermore, CBG is also known as either transcortin and is encoded by the gene SERPINA6, by which several variants with varying steroid-binding strength have been described [133,134,135,136,137]. A recent study suggested a link between SERPINA6 protease imbalance and COPD in the peripheral lung [138].
Although the binding and release of steroids to CBG is of importance to understanding steroid response during therapies, studies assessing the timing of steroid release or binding to CBG in distinct diseases are missing. There is also evidence that CBG deficiency can be transmitted from mother to child during pregnancy [139]. This finding might imply a novel epigenetic trait for steroid sensitivity but is at this stage only hypothetical. A recent review of CBG, its regulation, and its role in steroid function has been published by Hammond [140].

8. Discussion

Large-scale studies to define the precise timely function of all GR variants and modifications are needed if we want to develop personalized therapies for asthma, COPD, and other chronic inflammatory diseases, not only of the lung. Furthermore, such studies will help us to better understand the role of the GR in physiology and pathophysiology. Is it thinkable that the interaction of the GR with its complex-forming partner proteins underlies an unknown circadian regulation pattern and that this is off balance in chronic inflammatory lung diseases? Small changes in the timing of one of the components of the GR expression or of its signaling cascade might then have consequences for steroid effects and thus reduced steroid response.
To understand the complex nature of the GR network as the cause of reduced steroid sensitivity in chronic inflammatory lung diseases, studies of the precise timing of the GR’s location, activity status, and complexing partner proteins are implicated. Such studies must include the aspect of the many GR SNPs and GR isoforms.
Because each GR isoform and NR3C1 gene SNP might interact differently with other regulatory proteins over time and in specific conditions, the task will require the inclusion of genomic, transcriptomic, proteomic, and post-transcriptomics, as well as protein complex studies. Such studies will require large networks, manpower, and money to understand the networking of the GR. The promotor of the NR3C1 gene has eleven potential transcription start sites, and the GRα-A mRNA can be spliced and translated into seven GR protein variants, which is equal to seventy-seven structural different GR proteins [20]. These are subject to an uncertain number of post-translational modifications that might affect the activity status, location, or function of the GR [22,23,24,25,26,27,28,141,142,143]. It is also uncertain if only the GRα is subject to splicing, or if all other GR isoforms can also generate further variants with different functions, including steroid sensitivity. Thus, the number of study subjects that have to be included in ‘all-GR analysis’ would be enormous. These facts show the necessity of pre-selecting patients with well-defined specific GR variants and then analyzing the kinetics of expression, activity, and tissue or cell-type specific expression.
However, such an undertaking will gain new knowledge that provides not only a better understanding of the pathogenesis of chronic inflammatory lung diseases but it will also provide a better understanding of our physiology and of the cause of other diseases. Thereby, it will open new avenues for individual medicine and better therapies. The timing of therapeutics has been reported to improve the beneficial effects of steroids and other asthma drugs via GR function; unfortunately, these promising concepts have not yet been adapted as therapeutic strategies. To successfully apply such therapeutic regimes, it will also be necessary to explain the benefits to each patient (Figure 4). Furthermore, new methods for monitoring such therapies will be needed, a problem that has been assessed by others [144].

9. Conclusions

In summary, the effect of the nuclear GR largely depends on the presence of additional proteins including those that control its phosphorylation, degradation, structure, cytosol–nucleus transportation, and interacting transcription factors. All these interacting factors need to be present at a specific time and intracellular location to facilitate the GR action. A delay in any of them might lead to a lower GR action or failure and lead to chronic diseases. Unfortunately, such investigations are rare or missing.

Author Contributions

Both authors contributed equally to the conceptualization, writing, editing, and visualization of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

No material from humans or animal was used for writing this review.

Data Availability Statement

No original data used.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AP-1Activator protein 1
CBGCorticosteroid-binding globulin
C/EBPCCAAT enhancer-binding protein
COPDChronic obstructive pulmonary disease
CREBPCyclic AMP-binding protein
DNADeoxyribonucleic acid
DOAJDirectory of open-access journals
FKBPFK506-binding proteins
GCGlucocorticoid
GRGlucocorticoid receptor
GREGlucocorticoid response element
HSPHeat shock protein
mRNAMessenger ribonucleic acid
NFkBNuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells
SNPSingle-nucleotide polymorphism
TAC1Th2 high-inflammatory signature protein 1

References

  1. Global Initiative for Asthma: 2024 GINA Main Report. Available online: https://ginasthma.org/2024-report/ (accessed on 3 March 2025).
  2. American Lung Association: Asthma Trends and Burden. Available online: https://www.lung.org/research/trends-in-lung-disease/asthma-trends-brief/trends-and-burden (accessed on 3 March 2025).
  3. Oh, J.; Lee, M.; Kim, M.; Kim, H.J.; Lee, S.W.; Rhee, S.Y.; Koyanagi, A.; Smith, L.; Kim, M.S.; Lee, H.; et al. Incident allergic diseases in post-COVID-19 condition: Multinational cohort studies from South Korea, Japan and the UK. Nat. Commun. 2024, 15, 2830. [Google Scholar] [CrossRef] [PubMed]
  4. Celli, B.; Fabbri, L.; Criner, G.; Martinez, F.J.; Mannino, D.; Vogelmeier, C.; Montes de Oca, M.; Papi, A.; Sin, D.D.; Han, M.K.; et al. Definition and Nomenclature of Chronic Obstructive Pulmonary Disease: Time for Its Revision. Am. J. Respir. Crit. Care Med. 2022, 206, 1317–1325. [Google Scholar] [CrossRef]
  5. Henderson, I.; Caiazzo, E.; McSharry, C.; Guzik, T.J.; Maffia, P. Why do some asthma patients respond poorly to glucocorticoid therapy? Pharmacol. Res. 2020, 160, 105189. [Google Scholar] [CrossRef]
  6. Jacques, M.R.; Kuhn, B.T.; Albertson, T.E. Update on the pharmacological treatment of chronic obstructive pulmonary disease. Expert Opin. Pharmacother. 2024, 25, 1903–1922. [Google Scholar] [CrossRef]
  7. Sayers, I.; John, C.; Chen, J.; Hall, I.P. Genetics of chronic respiratory disease. Nat. Rev. Genet. 2024, 25, 534–547. [Google Scholar] [CrossRef] [PubMed]
  8. Quax, R.A.; Manenschijn, L.; Koper, J.W.; Hazes, J.M.; Lamberts, S.W.; van Rossum, E.F.; Feelders, R.A. Glucocorticoid sensitivity in health and disease. Nat. Rev. Endocrinol. 2013, 9, 670–686. [Google Scholar] [CrossRef]
  9. Blackhurst, G.; McElroy, P.K.; Fraser, R.; Swan, R.L.; Connell, J.M. Seasonal variation in glucocorticoid receptor binding characteristics in human mononuclear leucocytes. Clin. Endocrinol. 2001, 55, 683–688. [Google Scholar] [CrossRef] [PubMed]
  10. Cardinal, J.; Pretorius, C.J.; Ungerer, J.P. Biological and diurnal variation in glucocorticoid sensitivity detected with a sensitive in vitro dexamethasone suppression of cytokine production assay. J. Clin. Endocrinol. Metab. 2010, 95, 3657–3663. [Google Scholar] [CrossRef]
  11. Barnes, P.J.; Adcock, I.M. Glucocorticoid resistance in inflammatory diseases. Lancet 2009, 373, 1905–1917. [Google Scholar] [CrossRef]
  12. Martinez, G.J.; Appleton, M.; Kipp, Z.A.; Loria, A.S.; Min, B.; Hinds, T.D., Jr. Glucocorticoids, their uses, sexual dimorphisms, and diseases: New concepts, mechanisms, and discoveries. Physiol. Rev. 2024, 104, 473–532. [Google Scholar] [CrossRef]
  13. Brattsand, R.; Selroos, O. May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide? Pulm. Pharmacol. Ther. 2022, 77, 102167. [Google Scholar] [CrossRef] [PubMed]
  14. Allen, A.; Bareille, P.J.; Rousell, V.M. Fluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung absorption kinetics in man compared with inhaled fluticasone propionate. Clin. Pharmacokinet. 2013, 52, 37–42. [Google Scholar] [CrossRef] [PubMed]
  15. Levitt, D.G. Pharmacokinetics/pharmacodynamics of glucocorticoids: Modeling the glucocorticoid receptor dynamics and dose/response of commonly prescribed glucocorticoids. ADMET DMPK 2024, 12, 971–989. [Google Scholar] [CrossRef] [PubMed]
  16. Mostafa, M.M.; Rider, C.F.; Shah, S.; Traves, S.L.; Gordon, P.M.K.; Miller-Larsson, A.; Leigh, R.; Newton, R. Glucocorticoid-driven transcriptomes in human airway epithelial cells: Commonalities, differences and functional insight from cell lines and primary cells. BMC Med. Genom. 2019, 12, 29. [Google Scholar] [CrossRef]
  17. Mars, U.; d’Argy, R.; Hallbeck, K.; Miller-Larsson, A.; Edsbäcker, S. Tissue accumulation kinetics of ciclesonide-active metabolite and budesonide in mice. Basic Clin. Pharmacol. Toxicol. 2013, 112, 401–411. [Google Scholar] [CrossRef]
  18. Reichardt, S.D.; Amouret, A.; Muzzi, C.; Vettorazzi, S.; Tuckermann, J.P.; Lühder, F.; Reichardt, H.M. The Role of Glucocorticoids in Inflammatory Diseases. Cells 2021, 10, 2921. [Google Scholar] [CrossRef]
  19. Caramori, G.; Nucera, F.; Mumby, S.; Lo Bello, F.; Adcock, I.M. Corticosteroid resistance in asthma: Cellular and molecular mechanisms. Mol. Asp. Med. 2022, 85, 100969. [Google Scholar] [CrossRef]
  20. Lockett, J.; Inder, W.J.; Clifton, V.L. The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity. Endocr. Rev. 2024, 45, 593–624. [Google Scholar] [CrossRef]
  21. Clarisse, D.; Van Moortel, L.; Van Leene, C.; Gevaert, K.; De Bosscher, K. Glucocorticoid receptor signaling: Intricacies and therapeutic opportunities. Trends Biochem. Sci. 2024, 49, 431–444. [Google Scholar] [CrossRef]
  22. Moessmer, P.; Suren, T.; Majdic, U.; Dahiya, V.; Rutz, D.; Buchner, J.; Rief, M. Active unfolding of the glucocorticoid receptor by the Hsp70/Hsp40 chaperone system in single-molecule mechanical experiments. Proc. Natl. Acad. Sci. USA 2022, 119, e2119076119. [Google Scholar] [CrossRef]
  23. Hay, C.W.; Shanley, L.; Davidson, S.; Cowie, P.; Lear, M.; McGuffin, P.; Riedel, G.; McEwan, I.J.; MacKenzie, A. Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones. Psychoneuroendocrinology 2014, 47, 43–55. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  24. Martinelli, S.; Hafner, K.; Koedel, M.; Knauer-Arloth, J.; Gassen, N.C.; Binder, E.B. Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies. Int. J. Mol. Sci. 2024, 25, 12318. [Google Scholar] [CrossRef]
  25. National Institute of Health, National Center for Biotechnological Information. Available online: https://www.ncbi.nlm.nih.gov/gene/?term=NR3C1 (accessed on 3 March 2025).
  26. Koper, J.W.; van Rossum, E.F.; van den Akker, E.L. Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease. Steroids 2014, 92, 62–73. [Google Scholar] [CrossRef] [PubMed]
  27. Degtyareva, A.O.; Antontseva, E.V.; Merkulova, T.I. Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases. Int. J. Mol. Sci. 2021, 22, 6454. [Google Scholar] [CrossRef] [PubMed]
  28. Gebru, N.T.; Hill, S.E.; Blair, L.J. Genetically engineered mouse models of FK506-binding protein 5. J. Cell. Biochem. 2024, 125, e30374. [Google Scholar] [CrossRef]
  29. Singh, S.; Kularia, S.; Shukla, S.; Singh, M.; Kumar, M.; Sharma, A.K. A current review on animal models of anti-asthmatic drugs screening. Front. Pharmacol. 2025, 16, 1508460. [Google Scholar] [CrossRef]
  30. Fröhlich, E. Animals in Respiratory Research. Int. J. Mol. Sci. 2024, 25, 2903. [Google Scholar] [CrossRef]
  31. Johnson, J.L. FKBP51 functions in the regulation of circadian rhythm and Alzheimer’s disease. Cell Stress Chaperones 2025, 30, 81–83. [Google Scholar] [CrossRef]
  32. Gebru, N.T.; Beaulieu-Abdelahad, D.; Gulick, D.; Blair, L.J. FKBP51 overexpression in the corticolimbic system stabilizes circadian rhythms. Cell Stress Chaperones 2025, 30, 22–32. [Google Scholar] [CrossRef]
  33. Kim, M.J.; Choi, G.E.; Chae, C.W.; Lim, J.R.; Jung, Y.H.; Yoon, J.H.; Park, J.Y.; Han, H.J. Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR. Cell Death Dis. 2023, 14, 146. [Google Scholar] [CrossRef]
  34. Preston, R.; Chrisp, R.; Dudek, M.; Morais, M.R.P.T.; Tian, P.; Williams, E.; Naylor, R.W.; Davenport, B.; Pathiranage, D.R.J.; Benson, E.; et al. The glomerular circadian clock temporally regulates basement membrane dynamics and the podocyte glucocorticoid response. Kidney Int. 2025, 107, 99–115. [Google Scholar] [CrossRef]
  35. Welter, H.; Kreitmair, N.; Schneider, M.; Schneider, J.; Petkov, S.; Stepanov, Y.; Köhn, F.M.; Pickl, U.; Trottmann, M.; Fröhlich, T.; et al. Dexamethasone is a regulator of clock genes in testicular peritubular cells. Andrology 2024. online ahead of print. [Google Scholar] [CrossRef]
  36. Akinborewa, O.; Quattrocelli, M. Glucocorticoid receptor epigenetic activity in the heart. Epigenetics 2025, 20, 2468113. [Google Scholar] [CrossRef]
  37. Francia, M.; Bot, M.; Boltz, T.; De la Hoz, J.F.; Boks, M.; Kahn, R.S.; Ophoff, R.A. Fibroblasts as an in vitro model of circadian genetic and genomic studies. Mamm. Genome 2024, 35, 432–444. [Google Scholar] [CrossRef]
  38. Sundar, I.K.; Yao, H.; Sellix, M.T.; Rahman, I. Circadian clock-coupled lung cellular and molecular functions in chronic airway diseases. Am. J. Respir. Cell Mol. Biol. 2015, 53, 285–290. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  39. Kadmiel, M.; Cidlowski, J.A. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol. Sci. 2013, 34, 518–530. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  40. Kraft, M.; Vianna, E.; Martin, R.J.; Leung, D.Y. Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night. J. Allergy Clin. Immunol. 1999, 103 Pt 1, 66–71. [Google Scholar] [CrossRef] [PubMed]
  41. Kraft, M.; Hamid, Q.; Chrousos, G.P.; Martin, R.J.; Leung, D.Y. Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? Am. J. Respir. Crit. Care Med. 2001, 163, 1219–1225. [Google Scholar] [CrossRef]
  42. Burioka, N.; Fukuoka, Y.; Takata, M.; Endo, M.; Miyata, M.; Chikumi, H.; Tomita, K.; Kodani, M.; Touge, H.; Takeda, K.; et al. Circadian rhythms in the CNS and peripheral clock disorders: Function of clock genes: Influence of medication for bronchial asthma on circadian gene. J. Pharmacol. Sci. 2007, 103, 144–149. [Google Scholar] [CrossRef]
  43. Hayasaka, N.; Yaita, T.; Kuwaki, T.; Honma, S.; Honma, K.; Kudo, T.; Shibata, S. Optimization of dosing schedule of daily inhalant dexamethasone to minimize phase shifting of clock gene expression rhythm in the lungs of the asthma mouse model. Endocrinology 2007, 148, 3316–3326. [Google Scholar] [CrossRef]
  44. Gibbs, J.E.; Beesley, S.; Plumb, J.; Singh, D.; Farrow, S.; Ray, D.W.; Loudon, A.S. Circadian timing in the lung; a specific role for bronchiolar epithelial cells. Endocrinology 2009, 150, 268–276. [Google Scholar] [CrossRef]
  45. Shimba, A.; Ikuta, K. Glucocorticoids Regulate Circadian Rhythm of Innate and Adaptive Immunity. Front. Immunol. 2020, 11, 2143. [Google Scholar] [CrossRef]
  46. Smolensky, M.H.; Lemmer, B.; Reinberg, A.E. Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. Adv. Drug Deliv. Rev. 2007, 59, 852–882. [Google Scholar] [CrossRef]
  47. Lee, B.H.; Stallcup, M.R. Glucocorticoid receptor binding to chromatin is selectively controlled by the coregulator Hic-5 and chromatin remodeling enzymes. J. Biol. Chem. 2017, 292, 9320–9334. [Google Scholar] [CrossRef]
  48. Dendoncker, K.; Timmermans, S.; Van Looveren, K.; De Cauwer, L.; De Bosscher, K.; Libert, C. The nature of the GRE influences the screening for GR-activity enhancing modulators. PLoS ONE 2017, 12, e0181101. [Google Scholar] [CrossRef]
  49. Neophytou, A.M.; Lutzker, L.; Good, K.M.; Mann, J.K.; Noth, E.M.; Holm, S.M.; Costello, S.; Tyner, T.; Nadeau, K.C.; Eisen, E.A.; et al. Associations between prenatal and early-life air pollution exposure and lung function in young children: Exploring influential windows of exposure on lung development. Environ. Res. 2023, 222, 115415. [Google Scholar] [CrossRef]
  50. Damiani, I.; Solberg, E.H.; Iyer, M.; Cheng, P.; Weldy, C.S.; Kim, J.B. Environmental pollutants and atherosclerosis: Epigenetic mechanisms linking genetic risk and disease. Atherosclerosis 2025, 404, 119131. [Google Scholar] [CrossRef]
  51. Noguchi, T.; Makino, S.; Matsumoto, R.; Nakayama, S.; Nishiyama, M.; Terada, Y.; Hashimoto, K. Regulation of glucocorticoid receptor transcription and nuclear translocation during single and repeated immobilization stress. Endocrinology 2010, 151, 4344–4355. [Google Scholar] [CrossRef]
  52. Stortz, M.; Pecci, A.; Presman, D.M.; Levi, V. Unraveling the molecular interactions involved in phase separation of glucocorticoid receptor. BMC Biol. 2020, 18, 59. [Google Scholar] [CrossRef]
  53. Frank, F.; Liu, X.; Ortlund, E.A. Glucocorticoid receptor condensates link DNA-dependent receptor dimerization and transcriptional transactivation. Proc. Natl. Acad. Sci. USA 2021, 118, e2024685118. [Google Scholar] [CrossRef]
  54. Fang, L.; Wuptram, K.; Chen, D.; Li, H.; Huang, S.K.; Jin, C.; Yokoyama, K.K. Environmental-stress-induced Chromatin Regulation and its Heritability. J. Carcinog. Mutagen. 2014, 5, 22058. [Google Scholar] [CrossRef] [PubMed]
  55. Abell, N.S.; DeGorter, M.K.; Gloudemans, M.J.; Greenwald, E.; Smith, K.S.; He, Z.; Montgomery, S.B. Multiple causal variants underlie genetic associations in humans. Science 2022, 375, 1247–1254. [Google Scholar] [CrossRef] [PubMed]
  56. Álvarez-González, L.; Ruiz-Herrera, A. Evolution of 3D Chromatin Folding. Annu. Rev. Anim. Biosci. 2025, 13, 49–71. [Google Scholar] [CrossRef] [PubMed]
  57. Lei, J.; Zhao, M.; Deng, F.; Xu, T.; Ji, B.; Wang, X.; Zhang, M.; Sun, M.; Gao, Q. Prenatal dexamethasone exposure impaired vascular reactivity in adult male offspring cerebral arteries. J. Mol. Cell Cardiol. 2023, 181, 46–56. [Google Scholar] [CrossRef] [PubMed]
  58. Beck, D.; Cao, H.; Tian, F.; Huang, Y.; Jiang, M.; Zhao, H.; Tai, X.; Xu, W.; Kosasih, H.J.; Kealy, D.J.; et al. PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia. Nat. Commun. 2024, 15, 9697. [Google Scholar] [CrossRef]
  59. Takao, T.; Matsui, A.; Kikutake, C.; Kan-O, K.; Inoue, A.; Suyama, M.; Okamoto, I.; Ito, M. Maternal asthma imprints fetal lung ILC2s via glucocorticoid signaling leading to worsened allergic airway inflammation in murine adult offspring. Nat. Commun. 2025, 16, 631. [Google Scholar] [CrossRef]
  60. Zhao, Z.; Qin, J.; Pei, L.; He, Z.; Luo, H.; Magdalou, J.; Chen, L.; Wang, H. Articular damages in multi-generational female offspring due to prenatal caffeine exposure correlates with H3K9 deacetylation of TGFβ signaling pathway. Toxicology 2020, 442, 152533. [Google Scholar] [CrossRef]
  61. Burd, C.J.; Archer, T.K. Chromatin architecture defines the glucocorticoid response. Mol. Cell Endocrinol. 2013, 380, 25–31. [Google Scholar] [CrossRef]
  62. Bothe, M.; Buschow, R.; Meijsing, S.H. Glucocorticoid signaling induces transcriptional memory and universally reversible chromatin changes. Life Sci. Alliance 2021, 4, e202101080. [Google Scholar] [CrossRef] [PubMed]
  63. Lovem, M.I.; Huska, M.R.; Jurk, M.; Schöpflin, R.; Starick, S.R.; Schwahn, K.; Cooper, S.B.; Yamamoto, K.R.; Thomas-Chollier, M.; Vingron, M.; et al. Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation. Nucleic Acids Res. 2017, 45, 1805–1819. [Google Scholar] [CrossRef]
  64. Jubb, A.W.; Boyle, S.; Hume, D.A.; Bickmore, W.A. Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci. Cell Rep. 2017, 21, 3022–3031. [Google Scholar] [CrossRef]
  65. Wagh, K.; Stavreva, D.A.; Hager, G.L. Transcription dynamics and genome organization in the mammalian nucleus: Recent advances. Mol. Cell 2025, 85, 208–224. [Google Scholar] [CrossRef] [PubMed]
  66. Stortz, M.; Oses, C.; Lafuente, A.L.; Presman, D.M.; Levi, V. Catching the glucocorticoid receptor in the act: Lessons from fluorescence fluctuation methods. Biochem. Biophys. Res. Commun. 2025, 748, 151327. [Google Scholar] [CrossRef] [PubMed]
  67. Ibello, E.; Saracino, F.; Delle Cave, D.; Buonaiuto, S.; Amoroso, F.; Andolfi, G.; Corona, M.; Guardiola, O.; Colonna, V.; Sainz, B., Jr.; et al. Three-dimensional environment sensitizes pancreatic cancer cells to the anti-proliferative effect of budesonide by reprogramming energy metabolism. J. Exp. Clin. Cancer Res. 2024, 43, 165. [Google Scholar] [CrossRef]
  68. Jing, D.; Huang, Y.; Liu, X.; Sia, K.C.S.; Zhang, J.C.; Tai, X.; Wang, M.; Toscan, C.E.; McCalmont, H.; Evans, K.; et al. Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia. Cancer Cell 2018, 34, 906–921.e8. [Google Scholar] [CrossRef]
  69. Borin, C.; Pieters, T.; Serafin, V.; Ntziachristos, P. Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia. Hemasphere 2023, 7, e916. [Google Scholar] [CrossRef]
  70. Stolz, D.; Papakonstantinou, E.; Pascarella, M.; Jahn, K.; Siebeneichler, A.; Darie, A.M.; Herrmann, M.J.; Strobel, W.; Salina, A.; Grize, L.; et al. Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): A randomised, placebo-controlled, double-blind, investigator-initiated trial. Eur. Respir. J. 2023, 62, 2300218. [Google Scholar] [CrossRef]
  71. Zhou, Y.; Ampon, M.R.; Abramson, M.J.; James, A.L.; Maguire, G.P.; Wood-Baker, R.; Johns, D.P.; Marks, G.B.; Reddel, H.K.; Toelle, B.G. Prevalence and characteristics of adults with preserved ratio impaired spirometry (PRISm): Data from the BOLD Australia study. Chron. Respir. Dis. 2025, 22, 14799731241312687. [Google Scholar] [CrossRef]
  72. Buhumaid, R.; Alzaabi, A.; Mahboub, B.; Iqbal, M.N.; Alhameli, H.A.; Al-Mafrachi, M.G.; Dittrich, K.C.; Jaiganesh, T. The need for implementing a standardized, evidence-based emergency department discharge plan for optimizing adult asthma patient outcomes in the UAE, expert meeting report. Int. J. Emerg. Med. 2024, 17, 172. [Google Scholar] [CrossRef] [PubMed]
  73. van der Mark, L.B.; Lyklema, P.H.; Geskus, R.B.; Mohrs, J.; Bindels, P.J.; van Aalderen, W.M.; Ter Riet, G. A systematic review with attempted network meta-analysis of asthma therapy recommended for five to eighteen year olds in GINA steps three and four. BMC Pulm. Med. 2012, 12, 63. [Google Scholar] [CrossRef]
  74. Ortega, V.E.; Meyers, D.A.; Bleecker, E.R. Asthma pharmacogenetics and the development of genetic profiles for personalized medicine. Pharmgenomics Pers. Med. 2015, 8, 9–22. [Google Scholar] [CrossRef]
  75. Oakley, R.H.; Cidlowski, J.A. The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease. J. Allergy Clin. Immunol. 2013, 132, 1033–1044. [Google Scholar] [CrossRef] [PubMed]
  76. Zhou, J.; Cidlowski, J.A. The human glucocorticoid receptor: One gene, multiple proteins and diverse responses. Steroids 2005, 70, 407–417. [Google Scholar] [CrossRef] [PubMed]
  77. Lu, N.Z.; Cidlowski, J.A. Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol. Cell 2005, 18, 331–342. [Google Scholar] [CrossRef]
  78. Leventhal, S.M.; Lim, D.; Green, T.L.; Cantrell, A.E.; Cho, K.; Greenhalgh, D.G. Uncovering a multitude of human glucocorticoid receptor variants: An expansive survey of a single gene. BMC Genet. 2019, 20, 16. [Google Scholar] [CrossRef] [PubMed]
  79. Escoter-Torres, L.; Greulich, F.; Quagliarini, F.; Wierer, M.; Uhlenhaut, N.H. Anti-inflammatory functions of the glucocorticoid receptor require DNA binding. Nucleic Acids Res. 2020, 48, 8393–8407. [Google Scholar] [CrossRef]
  80. Vahedi, G. Remodeling the chromatin landscape in T lymphocytes by a division of labor among transcription factors. Immunol. Rev. 2021, 300, 167–180. [Google Scholar] [CrossRef]
  81. Oh, K.S.; Patel, H.; Gottschalk, R.A.; Lee, W.S.; Baek, S.; Fraser, I.D.C.; Hager, G.L.; Sung, M.H. Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action. Immunity 2017, 47, 298–309.e5. [Google Scholar] [CrossRef]
  82. Chang, W.T.; Hong, M.Y.; Chen, C.L.; Hwang, C.Y.; Tsai, C.C.; Chuang, C.C. Mutant glucocorticoid receptor binding elements on the interleukin-6 promoter regulate dexamethasone effects. BMC Immunol. 2021, 22, 24. [Google Scholar] [CrossRef]
  83. Oakley, R.H.; Ramamoorthy, S.; Foley, J.F.; Busada, J.T.; Lu, N.Z.; Cidlowski, J.A. Glucocorticoid receptor isoform-specific regulation of development, circadian rhythm, and inflammation in mice. FASEB J. 2018, 32, 5258–5271. [Google Scholar] [CrossRef]
  84. Duma, D.; Cidlowski, J.A. Generating diversity in glucocorticoid receptor signaling: Mechanisms, receptor isoforms, and post-translational modifications. Horm. Mol. Biol. Clin. Investig. 2010, 3, 319–328. [Google Scholar] [CrossRef]
  85. Oakley, R.H.; Sar, M.; Cidlowski, J.A. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J. Biol. Chem. 1996, 271, 9550–9559. [Google Scholar] [PubMed]
  86. Buoso, E.; Galasso, M.; Ronfani, M.; Serafini, M.M.; Lanni, C.; Corsini, E.; Racchi, M. Role of spliceosome proteins in the regulation of glucocorticoid receptor isoforms by cortisol and dehydroepiandrosterone. Pharmacol. Res. 2017, 120, 180–187. [Google Scholar] [CrossRef] [PubMed]
  87. Thomas-Chollier, M.; Watson, L.C.; Cooper, S.B.; Pufall, M.A.; Liu, J.S.; Borzym, K.; Vingron, M.; Yamamoto, K.R.; Meijsing, S.H. A naturally occurring insertion of a single amino acid rewires transcriptional regulation by glucocorticoid receptor isoforms. Proc. Natl. Acad. Sci. USA 2013, 110, 17826–17831. [Google Scholar] [CrossRef]
  88. Sinclair, D.; Webster, M.J.; Wong, J.; Weickert, C.S. Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development. Mol. Psychiatry 2011, 16, 504–515. [Google Scholar] [CrossRef]
  89. He, B.; Cruz-Topete, D.; Oakley, R.H.; Xiao, X.; Cidlowski, J.A. Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver. Mol. Cell Biol. 2015, 36, 714–730. [Google Scholar] [CrossRef] [PubMed]
  90. de Lange, P.; Segeren, C.M.; Koper, J.W.; Wiemer, E.; Sonneveld, P.; Brinkmann, A.O.; White, A.; Brogan, I.J.; de Jong, F.H.; Lamberts, S.W. Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells. Cancer Res. 2001, 61, 3937–3941. [Google Scholar] [CrossRef] [PubMed]
  91. Saif, Z.; Hodyl, N.A.; Stark, M.J.; Fuller, P.J.; Cole, T.; Lu, N.; Clifton, V.L. Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight. Placenta 2015, 36, 723–730. [Google Scholar] [CrossRef]
  92. Young, S.L.; Saif, Z.; Meakin, A.S.; McMaster, E.S.; Hayes, N.; Gallo, L.A.; Reid, N.; Moritz, K.M.; Clifton, V.L. Alterations to Placental Glucocorticoid Receptor Expression with Alcohol Consumption. Reprod. Sci. 2021, 28, 1390–1402. [Google Scholar] [CrossRef]
  93. Morgan, D.J.; Poolman, T.M.; Williamson, A.J.; Wang, Z.; Clark, N.R.; Ma’ayan, A.; Whetton, A.D.; Brass, A.; Matthews, L.C.; Ray, D.W. Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production. Sci. Rep. 2016, 6, 26419. [Google Scholar] [CrossRef]
  94. Beger, C.; Gerdes, K.; Lauten, M.; Tissing, W.J.; Fernandez-Munoz, I.; Schrappe, M.; Welte, K. Expression and structural analysis of glucocorticoid receptor isoform gamma in human leukaemia cells using an isoform-specific real-time polymerase chain reaction approach. Br. J. Haematol. 2003, 122, 245–252. [Google Scholar] [CrossRef]
  95. Haarman, E.G.; Kaspers, G.J.; Pieters, R.; Rottier, M.M.; Veerman, A.J. Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia 2004, 18, 530–537. [Google Scholar] [CrossRef] [PubMed]
  96. Duma, D.; Jewell, C.M.; Cidlowski, J.A. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J. Steroid Biochem. Mol. Biol. 2006, 102, 11–21. [Google Scholar] [CrossRef] [PubMed]
  97. Blind, R.D.; Garabedian, M.J. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes. J. Steroid Biochem. Mol. Biol. 2008, 109, 150–157. [Google Scholar] [CrossRef] [PubMed]
  98. Vazquez-Tello, A.; Halwani, R.; Hamid, Q.; Al-Muhsen, S. Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J. Clin. Immunol. 2013, 33, 466–478. [Google Scholar] [CrossRef] [PubMed]
  99. Wang, Z.; Wang, C.; Wang, Y.; Mo, B.; Wei, J.; Ma, L.; Rao, L.; Wang, J.; Yao, D.; Huang, J.; et al. E4BP4 facilitates glucocorticoid sensitivity of human bronchial epithelial cells via down-regulation of glucocorticoid receptor-beta. Cell Immunol. 2018, 334, 31–37. [Google Scholar] [CrossRef]
  100. Bansal, A.; Kooi, C.; Kalyanaraman, K.; Gill, S.; Thorne, A.; Chandramohan, P.; Necker-Brown, A.; Mostafa, M.M.; Milani, A.; Leigh, R.; et al. Synergy between Interleukin-1β, Interferon-γ, and Glucocorticoids to Induce TLR2 Expression Involves NF-κB, STAT1, and the Glucocorticoid Receptor. Mol. Pharmacol. 2023, 105, 23–38. [Google Scholar] [CrossRef]
  101. Zhang, Y.; Le, Y.; Ji, Y.; Yarde, S.; Yu, X.; Cheng, X. Activation of activator protein-1-fibroblast growth factor 21 signaling attenuates Cisplatin hepatotoxicity. Biochem. Pharmacol. 2021, 194, 114823. [Google Scholar] [CrossRef]
  102. Sevilla, L.M.; Jiménez-Panizo, A.; Alegre-Martí, A.; Estébanez-Perpiñá, E.; Caelles, C.; Pérez, P. Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways. Int. J. Mol. Sci. 2021, 22, 10049. [Google Scholar] [CrossRef]
  103. Rüdiger, J.J.; Roth, M.; Bihl, M.P.; Cornelius, B.C.; Johnson, M.; Ziesche, R.; Block, L.H. Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells. FASEB J. 2002, 16, 177–184. [Google Scholar] [CrossRef]
  104. Petty, E.; Pillus, L. Balancing chromatin remodeling and histone modifications in transcription. Trends Genet. 2013, 29, 621–629. [Google Scholar] [CrossRef]
  105. Xu, J.; Wang, W.; Xu, L.; Chen, J.Y.; Chong, J.; Oh, J.; Leschziner, A.E.; Fu, X.D.; Wang, D. Cockayne syndrome B protein acts as an ATP-dependent processivity factor that helps RNA polymerase II overcome nucleosome barriers. Proc. Natl. Acad. Sci. USA 2020, 117, 25486–25493. [Google Scholar] [CrossRef] [PubMed]
  106. Mustafi, P.; Hu, M.; Kumari, S.; Das, C.; Li, G.; Kundu, T.K. Phosphorylation-dependent association of human chromatin protein PC4 to linker histone H1 regulates genome organization and transcription. Nucleic Acids Res. 2022, 50, 6116–6136. [Google Scholar] [CrossRef] [PubMed]
  107. Roth, M.; Johnson, P.R.; Rüdiger, J.J.; King, G.G.; Ge, Q.; Burgess, J.K.; Anderson, G.; Tamm, M.; Black, J.L. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002, 360, 1293–1299. [Google Scholar] [CrossRef]
  108. Usmani, O.S.; Ito, K.; Maneechotesuwan, K.; Ito, M.; Johnson, M.; Barnes, P.J.; Adcock, I.M. Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. Am. J. Respir. Crit. Care Med. 2005, 172, 704–712. [Google Scholar] [CrossRef] [PubMed]
  109. Oliver, B.G.; Johnston, S.L.; Baraket, M.; Burgess, J.K.; King, N.J.; Roth, M.; Lim, S.; Black, J.L. Increased proinflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection. Respir. Res. 2006, 7, 71. [Google Scholar] [CrossRef]
  110. Miglino, N.; Roth, M.; Tamm, M.; Borger, P. House dust mite extract downregulates C/EBPα in asthmatic bronchial smooth muscle cells. Eur. Respir. J. 2011, 38, 50–58. [Google Scholar] [CrossRef]
  111. Yang, J.Q.; Rüdiger, J.J.; Hughes, J.M.; Goulet, S.; Gencay-Cornelson, M.M.; Borger, P.; Tamm, M.; Roth, M. Cell density and serum exposure modify the function of the glucocorticoid receptor C/EBP complex. Am. J. Respir. Cell Mol. Biol. 2008, 38, 414–422. [Google Scholar] [CrossRef]
  112. Lambers, C.; Kornauth, C.; Oberndorfer, F.; Boehm, P.M.; Tamm, M.; Klepetko, W.; Roth, M. Mechanism of anti-remodelling action of treprostinil in human pulmonary arterial smooth muscle cells. PLoS ONE 2018, 13, e0205195. [Google Scholar] [CrossRef]
  113. Roth, M.; Johnson, P.R.; Borger, P.; Bihl, M.P.; Rüdiger, J.J.; King, G.G.; Ge, Q.; Hostettler, K.; Burgess, J.K.; Black, J.L.; et al. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N. Engl. J. Med. 2004, 351, 560–574. [Google Scholar] [CrossRef]
  114. Carceller-Zazo, E.; Sevilla, L.M.; Pons-Alonso, O.; Chiner-Oms, Á.; Amazit, L.; An Vu, T.; Vitellius, G.; Viengchareun, S.; Comas, I.; Jaszczyszyn, Y.; et al. The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes. FASEB J. 2023, 37, e22709. [Google Scholar] [CrossRef]
  115. Haque, R.; Hakim, A.; Moodley, T.; Torrego, A.; Essilfie-Quaye, S.; Jazrawi, E.; Johnson, M.; Barnes, P.J.; Adcock, I.M.; Usmani, O.S. Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD. J. Allergy Clin. Immunol. 2013, 132, 1166–1173. [Google Scholar] [CrossRef] [PubMed]
  116. Quagliarini, F.; Mir, A.A.; Balazs, K.; Wierer, M.; Dyar, K.A.; Jouffe, C.; Makris, K.; Hawe, J.; Heinig, M.; Filipp, F.V.; et al. Cistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet. Mol. Cell 2019, 76, 531–545.e5. [Google Scholar] [CrossRef] [PubMed]
  117. Groeneweg, F.L.; Karst, H.; de Kloet, E.R.; Joëls, M. Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol. Cell Endocrinol. 2012, 350, 299–309. [Google Scholar] [CrossRef]
  118. Trebble, P.J.; Woolven, J.M.; Saunders, K.A.; Simpson, K.D.; Farrow, S.N.; Matthews, L.C.; Ray, D.W. A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function. J. Cell Sci. 2013, 126, 3159–3169. [Google Scholar] [CrossRef]
  119. Medar, M.L.; Andric, S.A.; Kostic, T.S. Stress-induced glucocorticoids alter the Leydig cells’ timing and steroidogenesis-related systems. Mol. Cell Endocrinol. 2021, 538, 111469. [Google Scholar] [CrossRef]
  120. Fadel, L.; Dacic, M.; Fonda, V.; Sokolsky, B.A.; Quagliarini, F.; Rogatsky, I.; Uhlenhaut, N.H. Modulating glucocorticoid receptor actions in physiology and pathology: Insights from coregulators. Pharmacol. Ther. 2023, 251, 108531. [Google Scholar] [CrossRef] [PubMed]
  121. Moore, W.C.; Bleecker, E.R.; Curran-Everett, D.; Erzurum, S.C.; Ameredes, B.T.; Bacharier, L.; Calhoun, W.J.; Castro, M.; Chung, K.F.; Clark, M.P.; et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J. Allergy Clin. Immunol. 2007, 119, 405–413. [Google Scholar] [CrossRef]
  122. Thomson, N.C.; Chaudhuri, R.; Livingston, E. Asthma and cigarette smoking. Eur. Respir. J. 2004, 24, 822–833. [Google Scholar] [CrossRef]
  123. Wu, X.; Jia, B.; Luo, X.; Wang, J.; Li, M. Glucocorticoid Alleviates Mechanical Stress-Induced Airway Inflammation and Remodeling in COPD via Transient Receptor Potential Canonical 1 Channel. Int. J. Chron. Obstruct. Pulmon. Dis. 2023, 18, 1837–1851. [Google Scholar] [CrossRef]
  124. Zhou, L.; Roth, M.; Papakonstantinou, E.; Tamm, M.; Stolz, D. Expression of glucocorticoid receptor and HDACs in airway smooth muscle cells is associated with response to steroids in COPD. Respir. Res. 2024, 25, 227. [Google Scholar] [CrossRef]
  125. Faiz, A.; Pavlidis, S.; Kuo, C.H.; Rowe, A.; Hiemstra, P.S.; Timens, W.; Berg, M.; Wisman, M.; Guo, Y.K.; Djukanović, R.; et al. Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD. Thorax 2023, 78, 335–343. [Google Scholar] [CrossRef] [PubMed]
  126. Hammond, G.L.; Smith, C.L.; Goping, I.S.; Underhill, D.A.; Harley, M.J.; Reventos, J.; Musto, N.A.; Gunsalus, G.L.; Bardin, C.W. Primary structure of human corticosteroid binding globulin, deduced from hepatic and pulmonary cDNAs, exhibits homology with serine protease inhibitors. Proc. Natl. Acad. Sci. USA 1987, 84, 5153–5157. [Google Scholar] [CrossRef] [PubMed]
  127. Gardill, B.R.; Vogl, M.R.; Lin, H.Y.; Hammond, G.L.; Muller, Y.A. Corticosteroid-binding globulin: Structure-function implications from species differences. PLoS ONE 2012, 7, e52759. [Google Scholar] [CrossRef] [PubMed]
  128. Siiteri, P.K.; Murai, J.T.; Hammond, G.L.; Nisker, J.A.; Raymoure, W.J.; Kuhn, R.W. The serum transport of steroid hormones. Recent Prog. Horm. Res. 1982, 38, 457–510. [Google Scholar] [CrossRef] [PubMed]
  129. Vermeulen, A.; Verdonck, L.; Kaufman, J.M. A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab. 1999, 84, 3666–3672. [Google Scholar] [CrossRef]
  130. Lin, H.Y.; Muller, Y.A.; Hammond, G.L. Molecular and structural basis of steroid hormone binding and release from corticosteroidbinding globulin. Mol. Cell. Endocrinol. 2010, 316, 3–12. [Google Scholar] [CrossRef]
  131. Bartalena, L.; Hammond, G.L.; Farsetti, A.; Flink, I.L.; Robbins, J. Interleukin-6 inhibits corticosteroid-binding globulin synthesis by human hepatoblastoma-derived (hep G2) cells. Endocrinology 1993, 133, 291–296. [Google Scholar] [CrossRef]
  132. Garrel, D.R. Corticosteroid-binding globulin during inflammation and burn injury: Nutritional modulation and clinical implications. Horm. Res. 1996, 45, 245–251. [Google Scholar] [CrossRef]
  133. Simard, M.; Hill, L.A.; Lewis, J.G.; Hammond, G.L. Naturally occurring mutations of human corticosteroid-binding globulin. J. Clin. Endocrinol. Metab. 2015, 100, E129–E139. [Google Scholar] [CrossRef]
  134. Lin, H.Y.; Underhill, C.; Lei, J.H.; Helander-Claesson, A.; Lee, H.Y.; Gardill, B.R.; Muller, Y.A.; Wang, H.; Hammond, G.L. High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects. J. Clin. Endocrinol. Metab. 2012, 97, E678–E686. [Google Scholar] [CrossRef]
  135. Meyer, E.J.; Spangenberg, L.; Ramírez, M.J.; De Sousa, S.M.C.; Raggio, V.; Torpy, D.J. CBG Montevideo: A Clinically Novel SERPINA6 Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin. J. Endocr. Soc. 2021, 5, bvab115. [Google Scholar] [CrossRef] [PubMed]
  136. Buss, C.; Schuelter, U.; Hesse, J.; Moser, D.; Phillips, D.I.; Hellhammer, D.; Meyer, J. Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency. J. Neural. Transm 2007, 114, 563–569. [Google Scholar] [CrossRef] [PubMed]
  137. Torpy, D.J.; Lundgren, B.A.; Ho, J.T.; Lewis, J.G.; Scott, H.S.; Mericq, V. CBG Santiago: A novel CBG mutation. J. Clin. Endocrinol. Metab. 2012, 97, E151–E155. [Google Scholar] [CrossRef] [PubMed]
  138. Di Stefano, A.; Nucera, F.; Rosani, U.; Brun, P.; Gnemmi, I.; Maniscalco, M.; D’Anna, S.E.; Leonardi, A.; Carriero, V.; Bertolini, F.; et al. Impaired SERPIN-Protease Balance in the Peripheral Lungs of Stable COPD Patients. Int. J. Mol. Sci. 2025, 26, 2832. [Google Scholar] [CrossRef]
  139. Navara, K.J. Programming of offspring sex ratios by maternal stress in humans: Assessment of physiological mechanisms using a comparative approach. J. Comp. Physiol. B Biochem. Syst. Environ. Physiol. 2010, 180, 785–796. [Google Scholar] [CrossRef]
  140. Hammond, G.L. Plasma steroid-binding proteins: Primary gatekeepers of steroid hormone action. J. Endocrinol. 2016, 230, R13–R25. [Google Scholar] [CrossRef]
  141. Fries, G.R.; Gassen, N.C.; Rein, T. The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease. Int. J. Mol. Sci. 2017, 18, 2614. [Google Scholar] [CrossRef]
  142. Petta, I.; Dejager, L.; Ballegeer, M.; Lievens, S.; Tavernier, J.; De Bosscher, K.; Libert, C. The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases. Microbiol. Mol. Biol. Rev. 2016, 80, 495–522. [Google Scholar] [CrossRef]
  143. Chalfun, G.; Reis, M.M.; de Oliveira, M.B.G.; de Araújo Brasil, A.; Dos Santos Salú, M.; da Cunha, A.J.L.A.; Prata-Barbosa, A.; de Magalhães-Barbosa, M.C. Perinatal stress and methylation of the NR3C1 gene in newborns: Systematic review. Epigenetics 2022, 17, 1003–1019. [Google Scholar] [CrossRef]
  144. Lesovaya, E.A.; Chudakova, D.; Baida, G.; Zhidkova, E.M.; Kirsanov, K.I.; Yakubovskaya, M.G.; Budunova, I.V. The long winding road to the safer glucocorticoid receptor (GR) targeting therapies. Oncotarget 2022, 13, 408–424. [Google Scholar] [CrossRef]
Biomedicines 13 01418 g001
Figure 1. Complex formation of the GR that regulates its ligand binding, cytosolic actions, and nuclear transport with subsequent transcriptional activity. Each of these steps can be delayed and lead to reduced or missing GR function and thus steroid insensitivity. The same applies to GR ligating proteins, as has been shown for the FKBP51 gene [23,24].
Figure 1. Complex formation of the GR that regulates its ligand binding, cytosolic actions, and nuclear transport with subsequent transcriptional activity. Each of these steps can be delayed and lead to reduced or missing GR function and thus steroid insensitivity. The same applies to GR ligating proteins, as has been shown for the FKBP51 gene [23,24].
Biomedicines 13 01418 g001
Biomedicines 13 01418 g002
Figure 2. Timing of post-translational GR modification on steroid sensitivity.
Figure 2. Timing of post-translational GR modification on steroid sensitivity.
Biomedicines 13 01418 g002
Biomedicines 13 01418 g003
Figure 3. NC3R1 gene structure and its implication on GR isoforms (adapted from Ref. [20]). GR isoform expression was suggested to depend on time and affect its function [93,94]. Distinct translation isoforms vary in the length of the N-terminal domain (NTD). Only one insertion was reported for the DNA-binding domain of the GR. Blue arrows indicate resulting GR-isoforms, the question mak indicates an unknown mechanism, the orange arrow indicates a distinct mechanism of RNA processing.
Figure 3. NC3R1 gene structure and its implication on GR isoforms (adapted from Ref. [20]). GR isoform expression was suggested to depend on time and affect its function [93,94]. Distinct translation isoforms vary in the length of the N-terminal domain (NTD). Only one insertion was reported for the DNA-binding domain of the GR. Blue arrows indicate resulting GR-isoforms, the question mak indicates an unknown mechanism, the orange arrow indicates a distinct mechanism of RNA processing.
Biomedicines 13 01418 g003
Biomedicines 13 01418 g004
Figure 4. Concept to determine the cause of individual steroid insensitivity and therapy.
Figure 4. Concept to determine the cause of individual steroid insensitivity and therapy.
Biomedicines 13 01418 g004
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lambers, C.; Roth, M. Glucocorticoid Insensitivity: Is It a Question of Time and Place? Biomedicines 2025, 13, 1418. https://doi.org/10.3390/biomedicines13061418

AMA Style

Lambers C, Roth M. Glucocorticoid Insensitivity: Is It a Question of Time and Place? Biomedicines. 2025; 13(6):1418. https://doi.org/10.3390/biomedicines13061418

Chicago/Turabian Style

Lambers, Christopher, and Michael Roth. 2025. "Glucocorticoid Insensitivity: Is It a Question of Time and Place?" Biomedicines 13, no. 6: 1418. https://doi.org/10.3390/biomedicines13061418

APA Style

Lambers, C., & Roth, M. (2025). Glucocorticoid Insensitivity: Is It a Question of Time and Place? Biomedicines, 13(6), 1418. https://doi.org/10.3390/biomedicines13061418

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop