Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγ3t activity Journal Article
| Authors: | Huh, J. R.; Leung, M. W. L.; Huang, P.; Ryan, D. A.; Krout, M. R.; Malapaka, R. R. V.; Chow, J.; Manel, N.; Ciofani, M.; Kim, S. V.; Cuesta, A.; Santori, F. R.; Lafaille, J. J.; Xu, H. E.; Gin, D. Y.; Rastinejad, F.; Littman, D. R. |
| Article Title: | Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγ3t activity |
| Abstract: | CD4+ T helper lymphocytes that express interleukin-17 (T H 17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T H 17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of TH 17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T H 17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORÎ 3t, which is required for induction of IL-17 transcription and for the manifestation of TH 17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORÎ 3t transcriptional activity. Digoxin inhibited murine TH 17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4+ T cells. Using these small-molecule compounds, we demonstrate that ROR 3t is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of ROR3t-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease. © 2011 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | unclassified drug; human cell; nonhuman; t lymphocyte; animal cell; mouse; cytology; mus; drug inhibition; gene expression; animal experiment; animal model; genetic transcription; cell differentiation; digoxin; enzyme activity; inhibitor; cd4+ t lymphocyte; murinae; cytokine production; genome; antiinflammatory activity; rodent; interleukin 17; immunity; th17 cell; drug protein binding; hexapoda; allergic encephalomyelitis; 20,22 dihydrodigoxin 21,23 diol; digoxin 21 salicylidene; orphan nuclear receptor; retinoic acid receptor related orphan nuclear receptor |
| Journal Title: | Nature |
| Volume: | 472 |
| Issue: | 7344 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2011-04-28 |
| Start Page: | 486 |
| End Page: | 490 |
| Language: | English |
| DOI: | 10.1038/nature09978 |
| PROVIDER: | scopus |
| PUBMED: | 21441909 |
| PMCID: | PMC3172133 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 23 June 2011" - "CODEN: NATUA" - "Source: Scopus" |
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