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Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 50192

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Dr. Marcel J.M. Schaaf

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Guest Editor

Institute for Biology Leiden (IBL), Leiden University, Leiden, The Netherlands
Interests: anti-inflammatory drugs; cortisol; glucocorticoid receptor; molecular endocrinology; single-molecule microscopy; steroid hormones; steroid receptor; zebrafish

Prof. Dr. Onno C. Meijer

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Guest Editor

Dept Medicine, div Endocrinology, Leiden University Medical Center (LUMC), The Netherlands
Interests: corticosteroids; cortisol; glucocorticoid receptor; molecular endocrinology; mineralocorticoid receptor; neuro-endocrinology; neurobiology; steroid hormones; steroid receptor

Special Issue Information

Dear Colleagues,

Glucocorticoids are widely prescribed immune-suppressive drugs, but their use is limited by the severity of their side effects and the occurrence of resistance. To overcome these issues, more research into the mechanisms of glucocorticoid action is required. The effects of glucocorticoids are mediated by the glucocorticoid receptor (GR), which acts as ligand-activated transcription factor, able to modulate gene transcription both positively and negatively. Traditionally, it was assumed that GRs interacting with other transcription factors, thereby inhibiting their activity, elicited the desired immune-suppressive effects and that GR binding to glucocorticoid response elements (GREs) in the DNA and subsequent transactivation of gene expression was responsible for the adverse effects. However, in recent years this view has been challenged and now appears to be a simplification. Furthermore, several mechanisms have been described that inhibit GR function and thereby cause glucocorticoid resistance. This Special Issue of Cells should further refine our current view of the mechanisms underlying the actions of glucocorticoids and the GR, aiming (eventually) at the development of novel immune-suppressive therapies, such as selective GR agonists and specific drug-targeting strategies. A broad area of research approaches will be covered, ranging from studies in vitro, in cultured cells, and animal models, to clinical studies.

Dr. Marcel J.M. Schaaf
Prof. Dr. Onno C. Meijer
Guest Editors

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Keywords

glucocorticoid
glucocorticoid receptor
immune-suppressive drugs
anti-inflammatory drugs
steroid receptor
selective glucocorticoid receptor agonists
glucocorticoid resistance

Published Papers (13 papers)

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Editorial

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5 pages, 189 KiB

Open AccessEditorial

Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research

by Marcel J. M. Schaaf and Onno C. Meijer

Cells 2022, 11(24), 4032; https://doi.org/10.3390/cells11244032 - 13 Dec 2022

Viewed by 914

Abstract

Due to their potent anti-inflammatory and immune-suppressive actions, glucocorticoids have been used in the treatment of inflammatory and autoimmune disease for more than 70 years [...] Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

Research

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20 pages, 3251 KiB

Open AccessArticle

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

by Glauben Landskron, Karen Dubois-Camacho, Octavio Orellana-Serradell, Marjorie De la Fuente, Daniela Parada-Venegas, Mirit Bitrán, David Diaz-Jimenez, Shuang Tang, John A. Cidlowski, Xiaoling Li, Hector Molina, Carlos M. Gonzalez, Daniela Simian, Jaime Lubascher, Victor Pola, Martín Montecino, Tjasso Blokzijl, Klaas Nico Faber, María-Julieta González, Rodrigo Quera and Marcela A. Hermoso Show full author list Hide full author list

Cells 2022, 11(12), 1905; https://doi.org/10.3390/cells11121905 - 12 Jun 2022

Cited by 5 | Viewed by 3234

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR^iKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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20 pages, 2961 KiB

Open AccessArticle

Two Types of Liposomal Formulations Improve the Therapeutic Ratio of Prednisolone Phosphate in a Zebrafish Model for Inflammation

by Yufei Xie, Panagiota Papadopoulou, Björn de Wit, Jan C. d’Engelbronner, Patrick van Hage, Alexander Kros and Marcel J. M. Schaaf

Cells 2022, 11(4), 671; https://doi.org/10.3390/cells11040671 - 15 Feb 2022

Cited by 4 | Viewed by 2144

Abstract

Glucocorticoids (GCs) are effective anti-inflammatory drugs, but their clinical use is limited by their side effects. Using liposomes to target GCs to inflammatory sites is a promising approach to improve their therapeutic ratio. We used zebrafish embryos to visualize the biodistribution of liposomes and to determine the anti-inflammatory and adverse effects of the GC prednisolone phosphate (PLP) encapsulated in these liposomes. Our results showed that PEGylated liposomes remained in circulation for long periods of time, whereas a novel type of liposomes (which we named AmbiMACs) selectively targeted macrophages. Upon laser wounding of the tail, both types of liposomes were shown to accumulate near the wounding site. Encapsulation of PLP in the PEGylated liposomes and AmbiMACs increased its potency to inhibit the inflammatory response. However, encapsulation of PLP in either type of liposome reduced its inhibitory effect on tissue regeneration, and encapsulation in PEGylated liposomes attenuated the activation of glucocorticoid-responsive gene expression throughout the body. Thus, by exploiting the unique possibilities of the zebrafish animal model to study the biodistribution as well as the anti-inflammatory and adverse effects of liposomal formulations of PLP, we showed that PEGylated liposomes and AmbiMACs increase the therapeutic ratio of this GC drug. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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11 pages, 688 KiB

Open AccessFeature PaperArticle

Glucocorticoids Are Not Associated with Bone Mineral Density in Patients with Polymyalgia Rheumatica, Giant Cell Arteritis and Other Vasculitides—Cross-Sectional Baseline Analysis of the Prospective Rh-GIOP Cohort

by Andriko Palmowski, Edgar Wiebe, Burkhard Muche, Sandra Hermann, Christian Dejaco, Eric L. Matteson and Frank Buttgereit

Cells 2022, 11(3), 536; https://doi.org/10.3390/cells11030536 - 4 Feb 2022

Cited by 4 | Viewed by 2349

Abstract

Background: Glucocorticoids (GCs) can cause osteoporosis (OP). Prior observational research on bone density and the effects of GCs in polymyalgia rheumatica (PMR) and vasculitides is scarce and inconclusive. Methods: Rh-GIOP is a prospective cohort study of bone health in patients with inflammatory rheumatic diseases. In this cross-sectional baseline analysis, we focused on patients with PMR and different forms of vasculitides. Multivariable linear regression was used to model the effect of current and cumulative GC intake on the minimum T-score at any site (mTs; at either lumbar spine or hip), with comprehensive adjustment for confounders. In separate models, GCs were modelled both as continuous and categorical predictors. Sensitivity analyses, stratifying by measurement site and disease, were conducted. Results: A total of 198 patients, with a mean age of 67.7 ± 11.4 years and a mean disease duration of 5.3 ± 6.3 years, were included. Most patients suffered from PMR (36%), giant cell arteritis (26%) or granulomatosis with polyangiitis (17%). Women comprised 66.7% of the patients, and 87.4% were currently taking GCs. The mean CRP was 13.2 ± 26.1 mg/L. OP diagnosed by dual energy X-ray absorptiometry (DXA) (T-score ≤ −2.5) was present in 19.7% of the patients. While 88% were taking vitamin D supplements, calcium supplementation (4%) and treatment with anti-resorptive agents (17%) were relatively infrequent. Only 7% had a vitamin D deficit. Neither current (β(continuous model) = −0.01, 97.5% CI –0.02 to 0.01; p(all models) ≥ 0.49) nor cumulative (β(continuous model) = 0.01, 97.5% CI −0.04 to 0.07; p(all models) ≥ 0.35) GC doses were associated with mTs in any model. CRP was not associated with mTs in any model (p(all models) ≥ 0.56), and no interaction between CRP and GC intake was observed (p for interaction(all models) ≥ 0.32). Across all analyses, lower body mass index (p(all models) ≤ 0.01), history of vertebral fractures (p(all models) ≤ 0.02) and proton-pump inhibitor intake (p(all models) ≤ 0.04) were associated with bone loss. Sensitivity analyses with femoral neck and lumbar spine T-scores as dependent variables led to similar results as the analysis that excluded patients with PMR. Conclusions: In this cohort of PMR and vasculitides, we found a similar prevalence of OP by DXA to the overall elderly German population. Vitamin D supplementation was very common, and vitamin D insufficiency was less frequent than expected in Germans. There was no association between current or cumulative GC intake, CRP and impaired bone density. Proton-pump inhibitors seem to be a major, but somewhat neglected, risk factor for OP and should be given more attention. Our findings require confirmation from longitudinal analyses of the Rh-GIOP and other cohorts. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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23 pages, 36748 KiB

Open AccessArticle

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

by Franziska Greulich, Kirsten Adele Bielefeld, Ronny Scheundel, Aikaterini Mechtidou, Benjamin Strickland and Nina Henriette Uhlenhaut

Cells 2022, 11(1), 28; https://doi.org/10.3390/cells11010028 - 23 Dec 2021

Cited by 7 | Viewed by 3328

Abstract

Glucocorticoids are potent anti-inflammatory drugs; however, their molecular mode of action remains complex and elusive. They bind to the glucocorticoid receptor (GR), a nuclear receptor that controls gene expression in almost all tissues in a cell type-specific manner. While GR’s transcriptional targets mediate beneficial reactions in immune cells, they also harbor the potential of adverse metabolic effects in other cell types such as hepatocytes. Here, we have profiled nascent transcription upon glucocorticoid stimulation in LPS-activated primary murine macrophages using 4sU-seq. We compared our results to publicly available nascent transcriptomics data from murine liver and bioinformatically identified non-coding RNAs transcribed from intergenic GR binding sites in a tissue-specific fashion. These tissue-specific enhancer RNAs (eRNAs) correlate with target gene expression, reflecting cell type-specific glucocorticoid responses. We further associate GR-mediated eRNA expression with changes in H3K27 acetylation and BRD4 recruitment in inflammatory macrophages upon glucocorticoid treatment. In summary, we propose a common mechanism by which GR-bound enhancers regulate target gene expression by changes in histone acetylation, BRD4 recruitment and eRNA expression. We argue that local eRNAs are potential therapeutic targets downstream of GR signaling which may modulate glucocorticoid response in a cell type-specific way. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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19 pages, 2176 KiB

Open AccessArticle

NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies

by Michał Pac, Natalia Krata, Barbara Moszczuk, Aleksandra Wyczałkowska-Tomasik, Beata Kaleta, Bartosz Foroncewicz, Witold Rudnicki, Leszek Pączek and Krzysztof Mucha

Cells 2021, 10(11), 3186; https://doi.org/10.3390/cells10113186 - 16 Nov 2021

Cited by 7 | Viewed by 2432

Abstract

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene (NR3C1) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs—rs6198, rs41423247 and rs17209237—in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN (p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs (p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy (p = 0.013) and IgAN (p = 0.021); and in the same groups treated with steroids (p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings (p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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15 pages, 1776 KiB

Open AccessFeature PaperArticle

Antihistamines Potentiate Dexamethasone Anti-Inflammatory Effects. Impact on Glucocorticoid Receptor-Mediated Expression of Inflammation-Related Genes

by Carlos Daniel Zappia, Valeria Torralba-Agu, Emiliana Echeverria, Carlos P. Fitzsimons, Natalia Fernández and Federico Monczor

Cells 2021, 10(11), 3026; https://doi.org/10.3390/cells10113026 - 5 Nov 2021

Cited by 7 | Viewed by 3085

Abstract

Antihistamines and glucocorticoids (GCs) are often used together in the clinic to treat several inflammation-related situations. Although there is no rationale for this association, clinical practice has assumed that, due to their concomitant anti-inflammatory effects, there should be an intrinsic benefit to their co-administration. In this work, we evaluated the effects of the co-treatment of several antihistamines on dexamethasone-induced glucocorticoid receptor transcriptional activity on the expression of various inflammation-related genes in A549 and U937 cell lines. Our results show that all antihistamines potentiate GCs’ anti-inflammatory effects, presenting ligand-, cell- and gene-dependent effects. Given that treatment with GCs has strong adverse effects, particularly on bone metabolism, we also examined the impact of antihistamine co-treatment on the expression of bone metabolism markers. Using MC3T3-E1 pre-osteoblastic cells, we observed that, though the antihistamine azelastine reduces the expression of dexamethasone-induced bone loss molecular markers, it potentiates osteoblast apoptosis. Our results suggest that the synergistic effect could contribute to reducing GC clinical doses, ineffective by itself but effective in combination with an antihistamine. This could result in a therapeutic advantage, as the addition of an antihistamine may reinforce the wanted effects of GCs, while related adverse effects could be diminished or at least mitigated. By modulating the patterns of gene activation/repression mediated by GR, antihistamines could enhance only the desired effects of GCs, allowing their effective dose to be reduced. Further research is needed to correctly determine the clinical scope, benefits, and potential risks of this therapeutic strategy. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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Review

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12 pages, 1182 KiB

Open AccessReview

Cell-Specific Immune Regulation by Glucocorticoids in Murine Models of Infection and Inflammation

by Lourdes Rocamora-Reverte, Andreas Villunger and G. Jan Wiegers

Cells 2022, 11(14), 2126; https://doi.org/10.3390/cells11142126 - 6 Jul 2022

Cited by 3 | Viewed by 2184

Abstract

Glucocorticoids (GC) are highly potent negative regulators of immune and inflammatory responses. Effects of GC are primarily mediated by the glucocorticoid receptor (GR) which is expressed by all cell types of the immune system. It is, therefore, difficult to elucidate how endogenous GC mediate their effects on immune responses that involve multiple cellular interactions between various immune cell subsets. This review focuses on endogenous GC targeting specific cells of the immune system in various animal models of infection and inflammation. Without the timed release of these hormones, animals infected with various microbes or challenged in inflammatory disease models succumb as a consequence of overshooting immune and inflammatory responses. A clearer picture is emerging that endogenous GC thereby act in a cell-specific and disease model-dependent manner, justifying the need to develop techniques that target GC to individual immune cell types for improved clinical application. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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22 pages, 10548 KiB

Open AccessReview

Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era

by Laura Kalfeist, Loïck Galland, Fanny Ledys, François Ghiringhelli, Emeric Limagne and Sylvain Ladoire

Cells 2022, 11(5), 770; https://doi.org/10.3390/cells11050770 - 22 Feb 2022

Cited by 27 | Viewed by 8348

Abstract

Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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22 pages, 9528 KiB

Open AccessFeature PaperReview

Dimerization of the Glucocorticoid Receptor and Its Importance in (Patho)physiology: A Primer

by Steven Timmermans, Jolien Vandewalle and Claude Libert

Cells 2022, 11(4), 683; https://doi.org/10.3390/cells11040683 - 15 Feb 2022

Cited by 13 | Viewed by 3602

Abstract

The glucocorticoid receptor (GR) is a very versatile protein that comes in several forms, interacts with many proteins and has multiple functions. Numerous therapies are based on GRs’ actions but the occurrence of side effects and reduced responses to glucocorticoids have motivated scientists to study GRs in great detail. The notion that GRs can perform functions as a monomeric protein, but also as a homodimer has raised questions about the underlying mechanisms, structural aspects of dimerization, influencing factors and biological functions. In this review paper, we are providing an overview of the current knowledge and insights about this important aspect of GR biology. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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27 pages, 1932 KiB

Open AccessReview

Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: From Physiology to Clinic

by Davide Marchi and Fredericus J. M. van Eeden

Cells 2021, 10(12), 3441; https://doi.org/10.3390/cells10123441 - 7 Dec 2021

Cited by 6 | Viewed by 6131

Abstract

Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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30 pages, 2209 KiB

Open AccessReview

The Role of Glucocorticoids in Inflammatory Diseases

by Sybille D. Reichardt, Agathe Amouret, Chiara Muzzi, Sabine Vettorazzi, Jan P. Tuckermann, Fred Lühder and Holger M. Reichardt

Cells 2021, 10(11), 2921; https://doi.org/10.3390/cells10112921 - 28 Oct 2021

Cited by 45 | Viewed by 7526

Abstract

For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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27 pages, 3542 KiB

Open AccessReview

Acquired Glucocorticoid Resistance Due to Homologous Glucocorticoid Receptor Downregulation: A Modern Look at an Age-Old Problem

by Lee-Maine L. Spies, Nicolette J. D. Verhoog and Ann Louw

Cells 2021, 10(10), 2529; https://doi.org/10.3390/cells10102529 - 24 Sep 2021

Cited by 18 | Viewed by 3515

Abstract

For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the onset of severe side-effects, chronic GC therapy often leads to the ligand-mediated downregulation of the GRα which, in turn, leads to a decrease in GC sensitivity, and effectively, the development of acquired GC resistance. Although the ligand-mediated downregulation of GRα is well documented, the precise factors which influence this process are not well understood and, thus, the development of an acquired GC resistance presents an ever-increasing challenge to the pharmaceutical industry. Recently, however, studies have correlated the dimerization status of the GRα with its ligand-mediated downregulation. Therefore, the current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC-mediated GRα downregulation. Full article

(This article belongs to the Special Issue Immune Modulations by Glucocorticoids: From Molecular Biology to Clinical Research)

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