Article Text

Original article
Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma
  1. Claire A Butler1,
  2. Stephen McQuaid2,
  3. Cliff C Taggart1,
  4. Sinead Weldon1,
  5. Richard Carter3,
  6. Grzegorz Skibinski1,
  7. Timothy J Warke1,
  8. David F Choy4,
  9. Lorcan P McGarvey1,
  10. Peter Bradding3,
  11. Joe R Arron4,
  12. Liam G Heaney1
  1. 1Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK
  2. 2Tissue Pathology, Belfast Health and Social Care Trust, Belfast, UK
  3. 3Department of Infection, Immunity and Inflammation, Maurice Shock Medical Sciences Building, Leicester, UK
  4. 4ITGR Biomarker Discovery, Genentech, Inc., South San Francisco, California, USA
  1. Correspondence to Dr Liam Heaney, Centre for Infection and Immunity, Queens University Belfast, Level 8, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK; l.heaney{at}


Rationale Upregulation of glucocorticoid receptor β (GRβ) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRβ has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRβ can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway.

Objectives To examine GRβ, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers.

Methods Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRβ antibody.

Measurements and main results Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRβ mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRβ antibody detected an additional ‘cross-reacting’ protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers.

Conclusions GRβ mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRβ and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRβ literature may be explained in part by clathrin cross-reactivity with commercial antibodies.

  • Glucocorticoid receptor β
  • clathrin
  • histone deacetylase
  • bronchial biopsy
  • severe asthma
  • airway epithelium
  • asthma
  • asthma mechanisms
  • COPD mechanisms
  • α1 antitrypsin deficiency
  • cystic fibrosis
  • cytokine biology
  • emphysema
  • innate immunity
  • lung proteases
  • macrophage biology
  • neutrophil biology
  • asthma genetics
  • COPD pathology
  • bronchoscopy
  • lung cancer
  • COPD exacerbations
  • cough/mechanisms/pharmacology
  • allergic lung disease
  • asthma pharmacology
  • eosinophil biology
  • asthma guidelines
  • COPD epidemiology

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  • Funding CB was supported by a grant from the Northern Ireland Chest, Heart and Stroke Association (reference no. 200645). Research in Leicester was conducted in laboratories and was part funded by ERDF #05567 and supported by a grant-in-aid from Genentech Inc., South San Francisco, California, USA.

  • Correction notice This article has been corrected since it was published Online First. The corresponding author is affiliated to Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK only.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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