Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]

Publication Date:
2018-07-27
Publisher:
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Print ISSN:
0026-895X
Electronic ISSN:
1521-0111
Topics:
Chemistry and Pharmacology
Medicine
Published by:
http://www.aspet.org/
_version_ 1836399015708590081
autor Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
beschreibung In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2 x glucocorticoid response element (2 x GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser 203 , Ser 211 , Ser 226 ) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2 x GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.
citation_standardnr 6310095
datenlieferant ipn_articles
feed_id 1938
feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-07-27
journaleissn 1521-0111
journalissn 0026-895X
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
quelle Molecular Pharmacology
relation http://molpharm.aspetjournals.org/cgi/content/short/94/3/1031?rss=1
search_space articles
shingle_author_1 Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
shingle_author_2 Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
shingle_author_3 Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
shingle_author_4 Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
shingle_catch_all_1 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2 x glucocorticoid response element (2 x GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser 203 , Ser 211 , Ser 226 ) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2 x GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.
Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_2 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2 x glucocorticoid response element (2 x GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser 203 , Ser 211 , Ser 226 ) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2 x GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.
Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_3 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2 x glucocorticoid response element (2 x GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser 203 , Ser 211 , Ser 226 ) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2 x GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.
Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_catch_all_4 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2 x glucocorticoid response element (2 x GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser 203 , Ser 211 , Ser 226 ) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2 x GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.
Rider, C. F., Altonsy, M. O., Mostafa, M. M., Shah, S. V., Sasse, S., Manson, M. L., Yan, D., Kärrman-Mardh, C., Miller-Larsson, A., Gerber, A. N., Giembycz, M. A., Newton, R.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0026-895X
0026895X
1521-0111
15210111
shingle_title_1 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
shingle_title_2 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
shingle_title_3 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
shingle_title_4 Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
timestamp 2025-06-30T23:36:14.853Z
titel Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
titel_suche Long-Acting {beta}2-Adrenoceptor Agonists Enhance Glucocorticoid Receptor (GR)-Mediated Transcription by Gene-Specific Mechanisms Rather Than Generic Effects via GR [Articles]
topic V
WW-YZ
uid ipn_articles_6310095