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An analysis of glucocorticoid receptor‐mediated gene expression in BEAS‐2B human airway epithelial cells identifies distinct, ligand‐directed, transcription profiles with implications for asthma therapeutics
Author(s) -
Joshi T,
Johnson M,
Newton R,
Giembycz M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13014
Subject(s) - glucocorticoid receptor , glucocorticoid , agonist , gene expression , hormone response element , inflammation , transcription factor , biology , immunology , regulation of gene expression , receptor , pharmacology , gene , microbiology and biotechnology , medicine , genetics , cancer , estrogen receptor , breast cancer
Background and Purpose International asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests that the therapeutic benefit of glucocorticoids is due to the trans activation and trans repression of anti‐inflammatory and pro‐inflammatory genes respectively. However, the extent to which clinically relevant glucocorticoids are equivalent in their ability to modulate gene expression is unclear. Experimental Approach A pharmacodynamics investigation of glucocorticoid receptor ( GR )‐mediated gene trans activation in BEAS‐2B human airway epithelial cells was performed using a glucocorticoid response element luciferase reporter coupled with an analysis of glucocorticoid‐inducible genes encoding proteins with anti‐inflammatory and adverse‐effect potential. Key Results Using trans activation as a functionally relevant output, a given glucocorticoid displayed a unique, gene expression ‘fingerprint’ where intrinsic efficacy and GR density were essential determinants. We showed that depending on the gene selected for analysis, a given glucocorticoid can behave as an antagonist, partial agonist, full agonist or even ‘super agonist’. In the likely event that different, tissue‐dependent gene expression profiles are reproduced in vivo , then the anti‐inflammatory and adverse‐effect potential of many glucocorticoids currently available as asthma therapeutics may not be equivalent. Conclusions and Implications The generation of gene expression ‘fingerprints’ in target and off‐target human tissues could assist the rational design of GR agonists with improved therapeutic ratios. This approach could identify compounds that are useful in the management of severe asthma and other inflammatory disorders where systemic exposure is desirable.