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

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2014 Nov 14

PMID 25393397

Citations 15

Authors

T Joshi

M Johnson

R Newton

M Giembycz

Affiliations

Soon will be listed here.

Abstract

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 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.

Experimental Approach: 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.

Key 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 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.

Citing Articles

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells.

Thorne A, Bansal A, Necker-Brown A, Mostafa M, Gao A, Georgescu A PLoS One. 2023; 18(6):e0286783.

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Genomic determinants implicated in the glucocorticoid-mediated induction of KLF9 in pulmonary epithelial cells.

Mostafa M, Bansal A, Michi A, Sasse S, Proud D, Gerber A J Biol Chem. 2020; 296:100065.

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Comparative efficacy of glucocorticoid receptor agonists on Th2 cell function and attenuation by progesterone.

Luchak A, Solomon L, Kanagalingam T, Vijeyakumaran M, Rowe B, Cameron L BMC Immunol. 2020; 21(1):54.

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GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life.

Louw A Front Immunol. 2019; 10:1693.

PMID: 31379877 PMC: 6653659. DOI: 10.3389/fimmu.2019.01693.

Long-Acting -Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR.

Rider C, Altonsy M, Mostafa M, Shah S, Sasse S, Manson M Mol Pharmacol. 2018; 94(3):1031-1046.

PMID: 29959223 PMC: 7385531. DOI: 10.1124/mol.118.112755.

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