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Lockett J, Inder WJ, Clifton VL. The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity. Endocr Rev 2024; 45:593-624. [PMID: 38551091 PMCID: PMC11244253 DOI: 10.1210/endrev/bnae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Indexed: 07/13/2024]
Abstract
Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.
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Affiliation(s)
- Jack Lockett
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4101, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD 4006, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Metro South Health, Woolloongabba, QLD 4102, Australia
| | - Warrick J Inder
- Faculty of Medicine, The University of Queensland, Herston, QLD 4006, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Metro South Health, Woolloongabba, QLD 4102, Australia
| | - Vicki L Clifton
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4101, Australia
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2
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Pofi R, Caratti G, Ray DW, Tomlinson JW. Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad? Endocr Rev 2023; 44:975-1011. [PMID: 37253115 PMCID: PMC10638606 DOI: 10.1210/endrev/bnad016] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/25/2023] [Accepted: 05/26/2023] [Indexed: 06/01/2023]
Abstract
It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.
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Affiliation(s)
- Riccardo Pofi
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - Giorgio Caratti
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford OX37LE, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK
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Restrained expression of canine glucocorticoid receptor splice variants α and P prognosticates fatal disease outcome in SIRS. Sci Rep 2021; 11:24505. [PMID: 34969952 PMCID: PMC8718537 DOI: 10.1038/s41598-021-03451-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 11/22/2021] [Indexed: 11/24/2022] Open
Abstract
Glucocorticoids play a central role in the inflammatory response and alleviate the symptoms in critically ill patients. The glucocorticoid action relies on the glucocorticoid receptor (GR) which translocates into the nucleus upon ligand-binding and regulates transcription of a battery of genes. Although the GR is encoded by a single gene, dozens of its splice variants have been described in diverse species. The GRα isoform encodes the full, functionally active protein that is composed of a transactivation, a DNA-binding, and a C-terminal ligand-binding domain. The second most highly expressed receptor variant, the GR-P, is formed by an intron retention that introduces an early stop codon and results in a probably dysfunctional protein with truncated ligand-binding domain. We described the canine ortholog of GR-P and showed that this splice variant is highly abundant in the peripheral blood of dogs. The level of cGRα and cGR-P transcripts are elevated in patients of SIRS and the survival rate is increased with elevated cGRα and cGR-P expression. The ratio of cGRα and cGR-P mRNA did not differ between the survivor and non-survivor patients; thus, the total GR expression is more pertinent than the relative expression of GR isoforms in assessment of the disease outcome.
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Martins CS, de Castro M. Generalized and tissue specific glucocorticoid resistance. Mol Cell Endocrinol 2021; 530:111277. [PMID: 33864884 DOI: 10.1016/j.mce.2021.111277] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/20/2022]
Abstract
Glucocorticoids (GCs) are steroid hormones that influence several physiologic functions and are among the most frequently prescribed drugs worldwide. Resistance to GCs has been observed in the context of the familial generalized GC resistance (Chrousos' syndrome) or tissue specific GC resistance in chronic inflammatory states. In this review, we have summarized the major factors that influence individual glucocorticoid sensitivity/resistance. The fine-tuning of GC action is determined in a tissue-specific fashion that includes the combination of different GC receptor promoters, translation initiation sites, splice isoforms, interacting proteins, post-translational modifications, and alternative mechanisms of signal transduction.
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Affiliation(s)
- Clarissa Silva Martins
- Department of Internal Medicine - Ribeirao Preto Medical School - University of Sao Paulo, Ribeirao Preto, SP, Brazil; School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil
| | - Margaret de Castro
- Department of Internal Medicine - Ribeirao Preto Medical School - University of Sao Paulo, Ribeirao Preto, SP, Brazil.
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Lipopolysaccharide Stress Induces Cryptic Exon Splice Variants of the Human Glucocorticoid Receptor. Shock 2019; 52:590-597. [DOI: 10.1097/shk.0000000000001318] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Leventhal SM, Lim D, Green TL, Cantrell AE, Cho K, Greenhalgh DG. Uncovering a multitude of human glucocorticoid receptor variants: an expansive survey of a single gene. BMC Genet 2019; 20:16. [PMID: 30736733 PMCID: PMC6368729 DOI: 10.1186/s12863-019-0718-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 01/23/2019] [Indexed: 12/26/2022] Open
Abstract
Background Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; however, significant variations in response to treatment have been demonstrated. Although the underlying mechanisms have yet to be fully understood, this variable response may be a result of alterations in human glucocorticoid receptor (hGR) expression and function. In addition to hGRα, the biologically active isoform, a screening of current databases and publications revealed five alternative splice isoforms and hundreds of variants that have been reported to date. Many of these changes in the hGR-coding gene, NR3C1, have been linked to pathophysiology. However, many studies focus on evaluating hGR expression in vitro or detecting previously reported variants. Results In this study, blood from healthy volunteers, burn and asthma patients, as well as from peripheral blood mononuclear cells isolated from leukoreduced donor whole blood, were screened for NR3C1 isoforms. We identified more than 1500 variants, including an additional 21 unique splice isoforms which contain 15 new cryptic exons. A dynamic database, named the Universal hGR (UhGR), was created to annotate and visualize the variants. Conclusion This identification of naturally occurring and stress-induced hGR isoforms, as well as the establishment of an hGR-specific database, may reveal new patterns or suggest areas of interest that will lead to the improved understanding of the human stress response system. Electronic supplementary material The online version of this article (10.1186/s12863-019-0718-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Stacey M Leventhal
- Shriners Hospitals for Children Northern California, Sacramento, California, USA
| | - Debora Lim
- Department of Surgery, University of California, Davis, Sacramento, California, USA
| | - Tajia L Green
- Shriners Hospitals for Children Northern California, Sacramento, California, USA
| | - Anna E Cantrell
- Department of Surgery, University of California, Davis, Sacramento, California, USA
| | - Kiho Cho
- Shriners Hospitals for Children Northern California, Sacramento, California, USA. .,Department of Surgery, University of California, Davis, Sacramento, California, USA.
| | - David G Greenhalgh
- Shriners Hospitals for Children Northern California, Sacramento, California, USA. .,Department of Surgery, University of California, Davis, Sacramento, California, USA.
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A Tri-Nucleotide Pattern in a 3' UTR Segment Affects The Activity of a Human Glucocorticoid Receptor Isoform. Shock 2018; 47:148-157. [PMID: 27660999 DOI: 10.1097/shk.0000000000000750] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We previously identified a truncated human glucocorticoid receptor (hGR) isoform of 118 amino acids, hGR-S1(-349A), that despite lacking the major functional domains, was more hyperactive after glucocorticoid treatment than the full-length receptor. Furthermore, its 3' untranslated region (UTR) was required. To dissect the underlying mechanisms for hyperactivity, a series of hGR isoforms with consecutive deletions in the 3' UTR were created to test their transactivation potential using reporter assays. The hGR-S1(-349A) isoform retaining 1303 bp of 3' UTR displayed unusually high activity with or without glucocorticoid stimulation. Unexpectedly, a complete loss of significant activity was observed with isoforms retaining 1293 bp or 1263 bp of 3' UTR. Analysis of the 20 bp region neighboring the 1293 bp site showed a pattern: 3'UTR termination at every third base pair in this region resulted in a loss of transactivation potential while the other sites retained hyperactivity with or without glucocorticoid stimulation. Variations in the activity of an hGR isoform, due to changes in the 3' UTR sequence configuration, may provide an important link in explaining inconsistent responses to glucocorticoid treatment in individuals and ultimately enable tailored, patient-specific care. Furthermore, understanding the mechanisms underlying the cyclic hyperactivity/loss of activity phenomenon may be a step toward identifying a novel mechanism of gene regulation.
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Abstract
PURPOSE OF REVIEW Interstitial lung disease (ILD) is comprised of a heterogeneous group of disorders with highly variable natural histories and response to therapies. Pharmacogenetics focuses on the variability in drug response because of the presence of genetic factors that influence drug metabolism or disease activity. In this article, we review relevant drug-specific and disease-specific polymorphisms that may influence therapeutic response, and then highlight a recently identified drug-gene interaction in patients with idiopathic pulmonary fibrosis (IPF). RECENT FINDINGS The emergence of high-throughput genomic technology has allowed for identification of gene polymorphisms associated with susceptibility to specific disease states, including IPF and several connective tissue diseases known to cause ILD. IPF risk loci span a diverse group of genes, while most associated with connective tissue disease are critical to immune signaling. A recent pharmacogenetic analysis of patients enrolled in an IPF clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy. SUMMARY Though few pharmacogenetic investigations have been conducted in patients with ILD to date, ample opportunities for pharmacogenetic exploration exist in this patient population. Such exploration will advance our understanding of specific ILDs and help usher in an era of personalized medicine.
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Moraitis AG, Block T, Nguyen D, Belanoff JK. The role of glucocorticoid receptors in metabolic syndrome and psychiatric illness. J Steroid Biochem Mol Biol 2017; 165:114-120. [PMID: 27002803 DOI: 10.1016/j.jsbmb.2016.03.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 03/14/2016] [Accepted: 03/18/2016] [Indexed: 11/23/2022]
Abstract
Glucocorticoids (GCs) are involved in a large number of the physiological changes associated with metabolic syndrome and certain psychiatric illness. Although significance is often given to the concentration of GC, its biological action is determined by the activation of intracellular GC receptors (GR). Genetic polymorphisms of the GR and the large array of GR related cofactors can directly or indirectly affect the pathophysiology and evolution of these conditions. This review will discuss the effects of GR mutations on metabolic syndrome and psychotic depression.
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Affiliation(s)
| | - Thaddeus Block
- Corcept Therapeutics, 149 Commonwealth, Menlo Park, CA, United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
| | - Dat Nguyen
- Corcept Therapeutics, 149 Commonwealth, Menlo Park, CA, United States
| | - Joseph K Belanoff
- Corcept Therapeutics, 149 Commonwealth, Menlo Park, CA, United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
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Green TL, Tung K, Lim D, Leventhal SM, Cho K, Greenhalgh DG. A novel human glucocorticoid receptor SNP results in increased transactivation potential. Biochem Biophys Rep 2016; 9:140-145. [PMID: 28955999 PMCID: PMC5614576 DOI: 10.1016/j.bbrep.2016.12.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 11/08/2016] [Accepted: 12/14/2016] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.
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Affiliation(s)
- Tajia L Green
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - Kelly Tung
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - Debora Lim
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - Stacey M Leventhal
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - Kiho Cho
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - David G Greenhalgh
- Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
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11
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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. [PMID: 27169854 DOI: 10.1128/mmbr.00064-15] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.
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12
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Nicolaides NC, Charmandari E, Chrousos GP, Kino T. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor. BMC Endocr Disord 2014; 14:71. [PMID: 25155432 PMCID: PMC4155765 DOI: 10.1186/1472-6823-14-71] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 07/31/2014] [Indexed: 12/11/2022] Open
Abstract
Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.
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Affiliation(s)
- Nicolas C Nicolaides
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens 11527, Greece
- Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
| | - Evangelia Charmandari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens 11527, Greece
- Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
| | - George P Chrousos
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens 11527, Greece
- Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
- Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tomoshige Kino
- Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 2089, USA
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Vandevyver S, Dejager L, Libert C. Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr Rev 2014; 35:671-93. [PMID: 24937701 DOI: 10.1210/er.2014-1010] [Citation(s) in RCA: 163] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glucocorticoids are among the most prescribed drugs worldwide for the treatment of numerous immune and inflammatory disorders. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. There are several GR isoforms resulting from alternative RNA splicing and translation initiation of the GR transcript. Additionally, these isoforms are all subject to several transcriptional, post-transcriptional, and post-translational modifications, all of which affect the protein's stability and/or function. In this review, we summarize recent knowledge on the distinct GR isoforms and the processes that generate them. We also review the importance of all known transcriptional, post-transcriptional, and post-translational modifications, including the regulation of GR by microRNAs. Moreover, we discuss the crucial role of the putative GR-bound DNA sequence as an allosteric ligand influencing GR structure and activity. Finally, we describe how the differential composition and distinct regulation at multiple levels of different GR species could account for the wide and diverse effects of glucocorticoids.
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Affiliation(s)
- Sofie Vandevyver
- Inflammation Research Center (S.V., L.D., C.L.), Flanders Institute for Biotechnology, B9052 Ghent, Belgium; and Department of Biomedical Molecular Biology (S.V., L.D., C.L.), Ghent University, B9052 Ghent, Belgium
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Boonen E, Van den Berghe G. Cortisol metabolism in critical illness: implications for clinical care. Curr Opin Endocrinol Diabetes Obes 2014; 21:185-92. [PMID: 24722172 DOI: 10.1097/med.0000000000000066] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Critical illness is uniformly characterized by elevated plasma cortisol concentrations, traditionally attributed exclusively to increased cortisol production driven by an activated hypothalamic pituitary adrenal axis. However, as plasma adrenocorticotropic hormone (ACTH) concentrations are often not elevated or even low during critical illness, alternative mechanisms must contribute. RECENT FINDINGS Recent investigations revealed that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the main cortisol metabolizing enzymes in liver and kidney. Furthermore, unlike previously inferred, cortisol production rate in critically ill patients was only moderately increased to less than double that of matched healthy subjects. In the face of low-plasma ACTH concentrations, these data suggest that other factors drive hypercortisolism during critical illness, which may suppress ACTH by feedback inhibition. These new insights add to the limitations of the current diagnostic tools to identify patients at risk of failing adrenal function during critical illness. They also urge to investigate the impact of lower hydrocortisone doses than those hitherto used. SUMMARY Recent novel insights reshape the current understanding of the hormonal stress response to critical illness and further underline the need for more studies to unravel the pathophysiology of adrenal (dys)functioning during critical illness.
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Affiliation(s)
- Eva Boonen
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
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15
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Iudicibus SD, Lucafò M, Martelossi S, Pierobon C, Ventura A, Decorti G. MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases. World J Gastroenterol 2013; 19:7947-54. [PMID: 24307788 PMCID: PMC3848142 DOI: 10.3748/wjg.v19.i44.7947] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 10/16/2013] [Accepted: 10/19/2013] [Indexed: 02/06/2023] Open
Abstract
In spite of the introduction in therapy of highly effective biological agents, glucocorticoids (GCs) are still employed to induce remission in moderate to severe inflammatory bowel diseases (IBD), but considerable inter-individual differences in their efficacy and side effects have been reported. The effectiveness of these drugs is indeed very variable and side effects, particularly severe in pediatric patients, are common and often unpredictable: the understanding of the complex gene regulation mediated by GCs could shed light on the causes of this variability. In this context, microRNAs (miRNAs) represent a new and promising field of research. miRNAs are small non-coding RNA molecules that suppress gene expression at post-transcriptional level, and are fine-tuning regulators of diverse biological processes, including the development and function of the immune system, apoptosis, metabolism and inflammation. Emerging data have implicated the deregulated expression of certain miRNA networks in the pathogenesis of autoimmune and inflammatory diseases, such as IBD. There is a great interest in the identification of the role of miRNAs in the modulation of pharmacological response; however, the association between miRNA and GC response in patients with IBD has not yet been evaluated in a prospective clinical study. The identification of miRNAs differently expressed as a consequence of GC treatment in comparison to diagnosis, represents an important innovative approach that could be translated into clinical practice. In this review we highlight the altered regulation of proteins involved in GC molecular mechanism by miRNAs, and their potential role as molecular markers useful for predicting in advance GC response.
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Strehl C, Buttgereit F. Optimized glucocorticoid therapy: teaching old drugs new tricks. Mol Cell Endocrinol 2013; 380:32-40. [PMID: 23403055 DOI: 10.1016/j.mce.2013.01.026] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/31/2013] [Accepted: 01/31/2013] [Indexed: 01/01/2023]
Abstract
Glucocorticoids (GCs) are commonly used in the treatment of a wide range of rheumatic and other inflammatory diseases. They exert their potent anti-inflammatory and immunosuppressive effects primarily via so called genomic mechanisms, mediated by the cytosolic glucocorticoid receptor (cGR). This mechanism of GC action can be divided into the transactivation and the transrepression processes. However, also rapid effects of GCs exist which are mediated by specific and unspecific non-genomic mechanisms. A clinical relevance of this mode of GC action is assumed for effects mediated by membrane-bound glucocorticoid receptors, but detailed knowledge on the underlying mechanisms is still missing. Great efforts have been made in the past to diminish GC-induced adverse effects, thus improving the benefit/risk ratio of the drugs. Besides approaches to improve the treatment with conventional glucocorticoids currently available to clinicians, new innovative GCs or GC receptor ligands are also being developed.
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Affiliation(s)
- Cindy Strehl
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
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17
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Single nucleotide polymorphisms and type of steroid impact the functional response of the human glucocorticoid receptor. J Surg Res 2013; 180:27-34. [DOI: 10.1016/j.jss.2012.12.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 11/30/2012] [Accepted: 12/03/2012] [Indexed: 11/19/2022]
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