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Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses

The Journal of experimental medicine, 2019-02, Vol.216 (2), p.384-406 [Peer Reviewed Journal]

This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. ;This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. 2019 ;ISSN: 0022-1007 ;EISSN: 1540-9538 ;DOI: 10.1084/jem.20180595 ;PMID: 30674564

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Title:
Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses
Author: Franco, Luis M ; Gadkari, Manasi ; Howe, Katherine N ; Sun, Jing ; Kardava, Lela ; Kumar, Parag ; Kumari, Sangeeta ; Hu, Zonghui ; Fraser, Iain D C ; Moir, Susan ; Tsang, John S ; Germain, Ronald N
Subjects: B-Lymphocytes - immunology ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - immunology ; Glucocorticoids - pharmacology ; Humans ; Interleukin-10 - immunology ; Receptors, Antigen, B-Cell - immunology ; Receptors, Glucocorticoid - immunology ; Signal Transduction - drug effects ; Signal Transduction - immunology ; Toll-Like Receptor 7 - immunology ; Transcription, Genetic - drug effects ; Transcription, Genetic - immunology
Is Part Of: The Journal of experimental medicine, 2019-02, Vol.216 (2), p.384-406
Description: Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.
Publisher: United States: Rockefeller University Press
Language: English
Identifier: ISSN: 0022-1007
EISSN: 1540-9538
DOI: 10.1084/jem.20180595
PMID: 30674564
Source: Open Access: PubMed Central
Geneva Foundation Free Medical Journals at publisher websites
MEDLINE

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Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses

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