Glucocorticoids induced down-regulation of glucocorticoid receptor mRNA expression in asthma

Vachier, Isabelle; Roux, Sébastiên; Chanez, Pascal; Loubatiere, J.; Térouanne, Béatrice; Nicolas, J.C.; Godard, P.

doi:10.1046/j.1365-2249.1996.d01-628.x

Cited by 18 publications

(8 citation statements)

References 19 publications

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“…Children with asthma expressed greater quantities of ␤ 2 AR and GR mRNA than healthy children. These findings are consistent with research showing that stable asthma is marked by elevated GR density on lymphocytes (18,19) and increased ␤ 2 AR on lymphocytes and lung tissue (20,21). The mechanism(s) underlying this phenomenon are unclear.…”

Section: Discussionsupporting

confidence: 91%

Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma

Miller

Chen

2006

Proc. Natl. Acad. Sci. U.S.A.

182

154

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Despite evidence that stressful experience can exacerbate the symptoms of asthma, little is known about the biological mechanisms through which this occurs. This study examined whether life stress reduces expression of the genes coding for the glucocorticoid receptor and the ␤2-adrenergic receptor. A total of 77 children were enrolled in the study (59% male; mean age, 13.5 years). Thirty-nine of them were physician-diagnosed with asthma, and 38 were healthy. After an in-depth interview regarding stressful experiences, leukocytes were collected through antecubital venipuncture, and real-time RT-PCR was used to quantify mRNA. Chronic stress was associated with reduced expression of mRNA for the ␤2-adrenergic receptor among children with asthma. In the sample of healthy children, however, the direction of this effect was reversed. The occurrence of a major life event in the 6 months before the study was not sufficient to influence patterns of gene expression. When such events occurred in the context of a chronic stressor, however, their association with patterns of gene expression was accentuated. Children with asthma who simultaneously experienced acute and chronic stress exhibited a 5.5-fold reduction in glucocorticoid receptor mRNA and a 9.5-fold reduction in ␤2-adrenergic receptor mRNA relative to children with asthma without comparable stressor exposure. These findings suggest that stressful experience diminishes expression of the glucocorticoid and ␤2-adrenergic receptor genes in children with asthma. To the extent that it diminishes sensitivity to the antiinflammatory properties of glucocorticoids or the bronchodilatory properties of ␤-agonists, this process could explain the increased asthma morbidity associated with stress. M ounting evidence indicates that stressful experience can exacerbate the symptoms of asthma in childhood (1-5). For example, in an 18-month prospective study of children with ongoing asthma, severe life events increased the risk of an attack by nearly 2-fold. The impact of life events was accentuated when they occurred in the context of a chronic stressor. Children exposed to high levels of acute and chronic stress showed a 3-fold increase in risk for an attack in the 2 weeks that followed (6, 7).Despite this robust pattern of findings, little is known about the responsible underlying mechanisms (1). Stressful experiences typically activate the hypothalamic-pituitary-adrenocortical and sympathetic-adrenal-medullary axes, leading to increased secretion of the hormones cortisol, epinephrine, and norepinephrine. Although these molecules are commonly thought to be mediators of stress-related disease (8), the role they play in linking stress and asthma is less clear. High levels of cortisol diminish inflammation in the airways and the periphery; similarly, ␤-adrenergic agonists such as epinephrine are potent bronchodilators. These observations suggest the paradoxical conclusion that stressful experiences should ameliorate rather than exacerbate symptoms of asthma (9, 10). The clinical data ...

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Section: Discussionsupporting

confidence: 91%

Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma

Miller

Chen

2006

Proc. Natl. Acad. Sci. U.S.A.

182

154

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“…Thus, most GR regulation studies have focused on analyses of GR mRNA expression (23,40). The close agreement between levels of GR␣ mRNA and protein evident in our study is consistent with predominantly transcriptional regulation of GR expression in human skeletal myoblasts.…”

Section: Discussionsupporting

confidence: 87%

“…11␤-HSD1 11-oxoreductase activity may, therefore, serve to maintain intracellular cortisol concentrations at higher levels than those present in the circulation. We have detected abundant levels of 11␤-HSD1 gene expression in cultured human skeletal myoblasts and demonstrated that it behaves exclusively as an 11-oxoreductase, with rates of activity similar to those reported in other isolated human cells (27,33,40). Unlike GR␣ expression, basal levels of 11␤-HSD1 expression in skeletal myoblasts are not associated with features of the metabolic syndrome.…”

Section: Discussionsupporting

confidence: 75%

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

et al. 2002

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Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-␣ and 11␤-hydroxysteroid dehydrogenase type I (11␤-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GR␣ and 11␤-HSD1 expression in skeletal myoblasts from men (n ‫؍‬ 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. Positive associations were evident between myoblast expression of GR␣ under basal conditions and levels of insulin resistance (r 2 ‫؍‬ 0.34, P < 0.05), BMI (r 2 ‫؍‬ 0.49, P < 0.01), percent body fat (r 2 ‫؍‬ 0.34, P < 0.02), and blood pressure (r 2 ‫؍‬ 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GR␣ expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11␤-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r 2 ‫؍‬ 0.68, P < 0.001), BMI (r 2 ‫؍‬ 0.63, P < 0.005), and blood pressure (r 2 ‫؍‬ 0.27, P < 0.05). Regulation of GR␣ and 11␤-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GR␣ and 11␤-HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.

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“…After a treatment with inhaled or oral GC, GR mRNA was shown to be downregulated in PBMC and endobronchial biopsies of mild to moderate asthmatics (30,31). We confirm this observation at the protein level: after a short course of oral GC, downregulation of GR␣ protein occurred in PBMC of previously untreated uncontrolled asthmatics.…”

Section: Discussionsupporting

confidence: 76%

Glucocorticoid Receptor α and β in Glucocorticoid Dependent Asthma

Gagliardo

Chanez

Vignola

et al. 2000

Am J Respir Crit Care Med

128

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Patients with glucocorticoid (GC)-dependent asthma present an ongoing inflammation of the airways despite chronic long-term treatment with oral GC. Interleukin (IL)-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been implicated in airway inflammation in severe asthma and their synthesis is normally repressed by GC. To further characterize the inflammatory process in GC-dependent asthma, we measured the release of IL-8 and GM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine GC-dependent asthmatics. We show that PBMC from GC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to GC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral GC, IL-8 and GM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of GC-dependent asthmatics was reduced after in vitro GC treatment (p < 0.002). We investigated whether the incapacity of GC to inhibit production of these cytokines in vivo was the result of a dysregulation of the glucocorticoid receptor (GR) in GC-dependent asthma. GRalpha and GRbeta are, respectively, the functional receptor and a putative dominant negative form of the receptor. Western blot and polymerase chain reaction (PCR) analyses indicated that GRalpha was expressed at similar level in all groups and was largely predominant over GRbeta. Thus, persistent release of IL-8 and GM-CSF in GC-dependent asthma is not associated with low expression of GRalpha or overexpression of GRbeta.

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Glucocorticoids induced down-regulation of glucocorticoid receptor mRNA expression in asthma

Cited by 18 publications

References 19 publications

Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma

Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

Glucocorticoid Receptor α and β in Glucocorticoid Dependent Asthma

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Glucocorticoids induced down-regulation of glucocorticoid receptor mRNA expression in asthma

Cited by 18 publications

References 19 publications

Life stress and diminished expression of genes encoding glucocorticoid receptor and β 2 -adrenergic receptor in children with asthma

Life stress and diminished expression of genes encoding glucocorticoid receptor and β 2 -adrenergic receptor in children with asthma

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

Glucocorticoid Receptor α and β in Glucocorticoid Dependent Asthma

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Product

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Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma

Life stress and diminished expression of genes encoding glucocorticoid receptor and β ₂ -adrenergic receptor in children with asthma