Increased number of glucocorticoid receptor-β–expressing cells in the airways in fatal asthma

Christodoulopoulos, Pota; Leung, Donald Y.M.; Elliott, Mark; Hogg, James C.; Muro, Shigeo; Toda, Masao; Laberge, Sophie; Hamid, Qutayba

doi:10.1067/mai.2000.109054

Cited by 130 publications

(85 citation statements)

References 25 publications

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“…Although the pathological role of GRb isoform is not well understood, previous reports demonstrate a strong correlation between steroid resistance in individuals with asthma and the expression levels of GRb (83). More importantly, increased GRb in the airways has been detected in patients who died of fatal asthma (84). Indeed, by its ability to act as a dominant-negative inhibitor of steroid action in other cell types (85), GRb has been associated with steroid resistance in different inflammatory diseases (76).…”

Section: Modulation Of Steroid Responsiveness By Tnf-a/ifn-gmentioning

confidence: 99%

Airway Smooth Muscle Cell as an Inflammatory Cell: Lessons Learned from Interferon Signaling Pathways

Tliba¹,

Amrani²

2008

Proceedings of the American Thoracic Society

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The present article will describe the potential role of airway smooth muscle (ASM) in mediating both deleterious/beneficial effects of interferons (IFNs) in asthma. First described as beneficial in treating the main features of asthma, the interplay between IFNs and ASM could explain their deleterious actions recently described in a number of different studies. Through multiple mechanisms, including the suppression of steroid action, the synergistic pro-inflammatory actions when combined with other cytokines, and the modulation of calcium metabolism, IFNs are now seen as critical mediators in the pathogenesis of asthma.

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Section: Modulation Of Steroid Responsiveness By Tnf-a/ifn-gmentioning

confidence: 99%

Airway Smooth Muscle Cell as an Inflammatory Cell: Lessons Learned from Interferon Signaling Pathways

Tliba¹,

Amrani²

2008

Proceedings of the American Thoracic Society

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“…In addition, hGR␤ protein has been reported in brain, lung, and heart tissue (23), although there is a contradictory report (25). Interestingly, the expression of hGR␤ has also been shown to be increased in glucocorticoid-resistant forms of asthma (3,9,16,30), ulcerative colitis (13), nasal polyposis (10), and chronic lymphocytic leukemia (19,29). In addition, we have previously shown that the expression of hGR␤ can be activated in cells by proinflammatory cytokines (36).…”

mentioning

confidence: 99%

Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive

Lewis‐Tuffin¹,

Jewell²,

Bienstock³

et al. 2007

Molecular and Cellular Biology

153

149

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“…However, the precise physiological role of GCR␤ has been controversial. Several studies have found elevated GCR␤ levels in association with GC insensitivity in a variety of the diseases (12)(13)(14)(15)(16). Some investigators have argued, however, that under physiological conditions the number of GCR␣ copies in the cell predominates over the number of copies of GCR␤, making it unlikely that it could have any functional inhibitory effect (17,18).…”

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confidence: 99%

Increased Glucocorticoid Receptor β Alters Steroid Response in Glucocorticoid-insensitive Asthma

Goleva

Eves

et al. 2006

Am J Respir Crit Care Med

199

163

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Rationale: Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma. Objectives: To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)␤ (a splicing variant, and dominant negative inhibitor of, the classic GCR␣) in controlling GCR␣ nuclear translocation and transactivation at a molecular level. Methods and Measurements: Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCR␣ cellular shuttling in response to 10 ؊6 M dexamethasone treatment and GCR␤ expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCR␤ mRNA on GCR␣ function were assessed. Main Results: Significantly reduced nuclear translocation of GCR␣ in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GCinsensitive asthma had significantly increased levels of cytoplasmic and nuclear GCR␤. It was demonstrated that GCR␣ nuclear translocation and its transactivation properties were proportionately reduced by level of viral transduction of the GCR␤ gene into the DO-11.10 cell line. RNA silencing of GCR␤ mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCR␣ transactivation. Conclusions: GC insensitivity is associated with loss of GCR␣ nuclear translocation in BAL cells and elevated GCR␤, which may inhibit GCR␣ transactivation in response to steroids.

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Increased number of glucocorticoid receptor-β–expressing cells in the airways in fatal asthma

Cited by 130 publications

References 25 publications

Airway Smooth Muscle Cell as an Inflammatory Cell: Lessons Learned from Interferon Signaling Pathways

Airway Smooth Muscle Cell as an Inflammatory Cell: Lessons Learned from Interferon Signaling Pathways

Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive

Increased Glucocorticoid Receptor β Alters Steroid Response in Glucocorticoid-insensitive Asthma

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