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.
OBJECTIVE
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 transactivation and transrepression 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.


METHODS
A pharmacodynamics investigation of glucocorticoid receptor (GR)-mediated gene transactivation 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.


RESULTS
Using transactivation 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
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.
Airways Inflammation Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Joshi
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Johnson
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Newton
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Giembycz
D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013329:Structure-Activity Relationship
D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid