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A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor

Glucocorticoids (GCs)—ligands of the glucocorticoid receptor (GR)—are widely used to treat inflammatory diseases, but suffer from significant side effects and poor responsiveness in certain patient populations. Identification of chemical GR modulators may provide insights into the regulatory mechani...

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Autores principales: Jiang, Xiaofeng, Dahlin, Amber, Weiss, Scott T., Tantisira, Kelan, Lu, Quan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547123/
https://www.ncbi.nlm.nih.gov/pubmed/28785063
http://dx.doi.org/10.1038/s41598-017-07565-2
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author Jiang, Xiaofeng
Dahlin, Amber
Weiss, Scott T.
Tantisira, Kelan
Lu, Quan
author_facet Jiang, Xiaofeng
Dahlin, Amber
Weiss, Scott T.
Tantisira, Kelan
Lu, Quan
author_sort Jiang, Xiaofeng
collection PubMed
description Glucocorticoids (GCs)—ligands of the glucocorticoid receptor (GR)—are widely used to treat inflammatory diseases, but suffer from significant side effects and poor responsiveness in certain patient populations. Identification of chemical GR modulators may provide insights into the regulatory mechanisms of anti-inflammatory functions of GR and help improve GC-based therapy. Here we report the development and application of a high-throughput screening to identify compounds that either enhance or suppress the anti-inflammatory effect of GR function. Using a cell-based GR activity assay that measures Dexamethasone (Dex)-mediated NF-κB repression, we have screened ~8,000 compounds and identified several compounds that suppressed GR activity, including multiple GSK3β inhibitors and anti-cancer agent camptothecin. Notably, we also identified two kinase IKK2 inhibitors, including TPCA-1, as GR enhancers that improve the anti-inflammatory effect of GR. In particular, TPCA-1 augmented the activity of Dex in NF-κB repression by attenuating GR down-regulation. Consistent with the observation, siRNA-mediated IKK2 knockdown decreased GR down-regulation and increased GR expression. Together, our results identified chemical compounds as novel modulators of GR and revealed an unexpected role for IKK2 in GR down-regulation. Furthermore, we have established a high-throughput screening platform for discovering GR-modulating compounds that may be repurposed to improve current GC-based therapies.
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spelling pubmed-55471232017-08-09 A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor Jiang, Xiaofeng Dahlin, Amber Weiss, Scott T. Tantisira, Kelan Lu, Quan Sci Rep Article Glucocorticoids (GCs)—ligands of the glucocorticoid receptor (GR)—are widely used to treat inflammatory diseases, but suffer from significant side effects and poor responsiveness in certain patient populations. Identification of chemical GR modulators may provide insights into the regulatory mechanisms of anti-inflammatory functions of GR and help improve GC-based therapy. Here we report the development and application of a high-throughput screening to identify compounds that either enhance or suppress the anti-inflammatory effect of GR function. Using a cell-based GR activity assay that measures Dexamethasone (Dex)-mediated NF-κB repression, we have screened ~8,000 compounds and identified several compounds that suppressed GR activity, including multiple GSK3β inhibitors and anti-cancer agent camptothecin. Notably, we also identified two kinase IKK2 inhibitors, including TPCA-1, as GR enhancers that improve the anti-inflammatory effect of GR. In particular, TPCA-1 augmented the activity of Dex in NF-κB repression by attenuating GR down-regulation. Consistent with the observation, siRNA-mediated IKK2 knockdown decreased GR down-regulation and increased GR expression. Together, our results identified chemical compounds as novel modulators of GR and revealed an unexpected role for IKK2 in GR down-regulation. Furthermore, we have established a high-throughput screening platform for discovering GR-modulating compounds that may be repurposed to improve current GC-based therapies. Nature Publishing Group UK 2017-08-07 /pmc/articles/PMC5547123/ /pubmed/28785063 http://dx.doi.org/10.1038/s41598-017-07565-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jiang, Xiaofeng
Dahlin, Amber
Weiss, Scott T.
Tantisira, Kelan
Lu, Quan
A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title_full A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title_fullStr A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title_full_unstemmed A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title_short A high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
title_sort high-throughput chemical screen identifies novel inhibitors and enhancers of anti-inflammatory functions of the glucocorticoid receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547123/
https://www.ncbi.nlm.nih.gov/pubmed/28785063
http://dx.doi.org/10.1038/s41598-017-07565-2
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