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

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

  • J Exp Med. 2019 Feb 4;216(2):384-406. doi: 10.1084/jem.20180595.
Luis M Franco 1,  Manasi Gadkari 2,  Katherine N Howe 3,  Jing Sun 2,  Lela Kardava 4,  Parag Kumar 5,  Sangeeta Kumari 2,  Zonghui Hu 6,  Iain D C Fraser 2,  Susan Moir 4,  John S Tsang 2 7,  Ronald N Germain 2
Affiliations

Affiliations

  • 1 Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD luis.franco@nih.gov.
  • 2 Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 3 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 4 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 5 Clinical Pharmacokinetics Research Unit, Clinical Center, National Institutes of Health, Bethesda, MD.
  • 6 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 7 Center for Human Immunology, National Institutes of Health, Bethesda, MD.
PMID: 30674564 DOI: 10.1084/jem.20180595
Abstract

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.

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