Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma

Butler, Claire A.; McQuaid, Stephen; Taggart, Clifford C.; Weldon, Sinéad; Carter, Richard; Skibiński, Grzegorz; Warke, T.J.; Choy, David F.; McGarvey, Lorcan; Bradding, Peter; Arron, Joseph R.; Heaney, Liam G.

doi:10.1136/thoraxjnl-2011-200760

Cited by 59 publications

(50 citation statements)

References 36 publications

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“…GR-α is ubiquitously expressed and is responsible for the induction and Nanzer et al 16 repression of target genes, while GR-ß is expressed at much lower levels and is a dominant negative inhibitor of GR-α. Increased expression of GR-ß has been linked with severe asthma in some studies (42,46), and a recent study suggested that IL-17A and IL-17F increase the expression of GR-ß, an effect that was more prominent in asthmatics than in healthy controls (23). These data imply a complex and potentially detrimental relationship between IL-17A, steroid treatment and responsiveness in severe asthma, on which vitamin D may have a positive impact.…”

Section: Nanzer Et Al 15mentioning

confidence: 89%

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Nanzer

Chambers

Ryanna

et al. 2013

Journal of Allergy and Clinical Immunology

165

144

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Section: Nanzer Et Al 15mentioning

confidence: 89%

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Nanzer

Chambers

Ryanna

et al. 2013

Journal of Allergy and Clinical Immunology

165

144

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“…HDACs are critical proteins that repress the production of proinflammatory cytokines (9,11), and HDAC2 has been reported to be required for corticosteroid-mediated anti-inflammatory activity (18). HDAC2 expression and activity is regulated through PI3K-␦/Akt and, specifically, a decrease in PAkt levels may increase the expression of HDAC2 (25).…”

Section: Discussionmentioning

confidence: 99%

Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression

Sun

Zhang

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 g/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)␣ expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-␦/Akt pathway and enhancing GR␣ expression.

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“…[10,21,22] Healthy controls (n=17), mild/moderate asthmatics (n=29) and severe asthmatics (n=18) were recruited from two UK specialist asthma centres, Belfast City Hospital and Glenfield Hospital, Leicester (demographic characteristics shown in Table 1). …”

Section: Patient Cohortmentioning

confidence: 99%

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Doran

Choy²,

Shikotra³

et al. 2016

Eur Respir J

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Take home message:Persistent airway eosinophilia/Th2 inflammation in severe asthma is associated with reduced epithelial SOCS1 expression. ABSTRACTSevere asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the JAK-STAT pathway.We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, qPCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating IL-13 signalling in vitro.

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Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma

Abstract: Rationale Upregulation of glucocorticoid receptor

Cited by 59 publications

References 36 publications

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

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