Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans

Cao, Yun; Bender, Ingrid; Konstantinidis, Athanasios; Shin, Soon Cheon; Jewell, Christine M.; Cidlowski, John A.; Schleimer, Robert P.; Lu, Nanxi

doi:10.1182/blood-2012-05-432336

Cited by 62 publications

(54 citation statements)

References 41 publications

(85 reference statements)

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“…Our results are surprising in lieu of the extensive literature demonstrating the inhibitory effects of glucocorticoids on adult beta cells [15]. The reason as to why glucocorticoid signaling might elicit different outcomes in young beta cells versus their adult counterparts is currently unknown, but we note that mature (but not immature) dendritic cells are susceptible to apoptotic signals induced by glucocorticoids due to the expression of different translational isoforms of GR [47].…”

contrasting

confidence: 59%

Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro

Ghazalli

Walker

et al. 2018

Stem Cells and Development

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Pluripotent stem cells may serve as an alternative source of beta-like cells for replacement therapy of type 1 diabetes; however, the beta-like cells generated in many differentiation protocols are immature. The maturation of endogenous beta cells involves an increase in insulin expression starting in late gestation and a gradual acquisition of the abilities to sense glucose and secrete insulin by week 2 after birth in mice; however, what molecules regulate these maturation processes are incompletely known. In this study, we aim to identify small molecules that affect immature beta cells. A cell-based assay, using pancreatic beta-like cells derived from murine embryonic stem (ES) cells harboring a transgene containing an insulin 1-promoter driven enhanced green fluorescent protein reporter, was used to screen a compound library (NIH Clinical Collection-003). Cortisone, a glucocorticoid, was among five positive hit compounds. Quantitative reverse transcription-polymerase chain reaction analysis revealed that glucocorticoids enhance the gene expression of not only insulin 1 but also glucose transporter-2 (Glut2; Slc2a2) and glucokinase (Gck), two molecules important for glucose sensing. Mifepristone, a pharmacological inhibitor of glucocorticoid receptor (GR) signaling, reduced the effects of glucocorticoids on Glut2 and Gck expression. The effects of glucocorticoids on ES-derived cells were further validated in immature primary islets. Isolated islets from 1-week-old mice had an increased Glut2 and Gck expression in response to a 4-day treatment of exogenous hydrocortisone in vitro. Gene deletion of GR in beta cells using rat insulin 2 promoter-driven Cre crossed with GR flox/flox mice resulted in a reduced gene expression of Glut2, but not Gck, and an abrogation of insulin secretion when islets were incubated in 0.5 mM d-glucose and stimulated by 17 mM d-glucose in vitro. These results demonstrate that glucocorticoids positively regulate glucose sensors in immature murine beta-like cells.

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confidence: 59%

Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro

Ghazalli

Walker

et al. 2018

Stem Cells and Development

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“…The GR gene produces several GR isoforms, which we have previously shown to have distinct abilities to induce apoptosis (19, 20, 25). To determine whether GR isoforms play a role in the distinct glucocorticoid sensitivity of Th subsets, GR levels were determined in differentiated murine Th cells.…”

Section: Resultsmentioning

confidence: 99%

BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

Banuelos

Shin

Cao

et al. 2016

Allergy

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Background Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. Methods Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. Results Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. Conclusion Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma.

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“…However, trabecular meshwork cells from the human eye preferentially express the GRα-C and GRα-D isoforms (88). In addition, immature dendritic cells predominantly express the GRα-D isoforms whereas mature dendritic cells predominantly express the GRα-A subtype (89). In rodents, GRα-C isoforms are highest in pancreas and colon and the GRα-D subtypes are highest in spleen and lung (15).…”

Section: Gr Translational Isoformsmentioning

confidence: 99%

The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease

Oakley¹,

Cidlowski²

2013

Journal of Allergy and Clinical Immunology

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748

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Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiological processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematological cancers. The physiological and pharmacological actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes by direct binding to DNA response elements and/or by physically associating with other transcription factors. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by alternative splicing and alternative translation initiation mechanisms. Post-translational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here, we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues.

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Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans

Abstract: • Mature, but not immature, dendritic cells are sensitive to glucocorticoid-induced apoptosis.• Mature, but not immature, dendritic cells express proapoptotic glucocorticoid receptor translational isoforms.

Cited by 62 publications

References 41 publications

Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro

Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro

BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease

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