Publication Date:
2011-03-29
Description:
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 T(H)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 RORgammat, which is required for induction of IL-17 transcription and for the manifestation of T(H)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 RORgammat transcriptional activity. Digoxin inhibited murine T(H)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 RORgammat 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 RORgammat-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huh, Jun R -- Leung, Monica W L -- Huang, Pengxiang -- Ryan, Daniel A -- Krout, Michael R -- Malapaka, Raghu R V -- Chow, Jonathan -- Manel, Nicolas -- Ciofani, Maria -- Kim, Sangwon V -- Cuesta, Adolfo -- Santori, Fabio R -- Lafaille, Juan J -- Xu, H Eric -- Gin, David Y -- Rastinejad, Fraydoon -- Littman, Dan R -- 2R01GM55217/GM/NIGMS NIH HHS/ -- F32GM0860552/GM/NIGMS NIH HHS/ -- R01 AI080885/AI/NIAID NIH HHS/ -- R01AI080885/AI/NIAID NIH HHS/ -- R01GM058833/GM/NIGMS NIH HHS/ -- R01GM067659/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 28;472(7344):486-90. doi: 10.1038/nature09978. Epub 2011 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21441909" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Autoimmune Diseases/drug therapy/immunology/pathology
;
Autoimmunity/drug effects/immunology
;
Cell Differentiation/*drug effects
;
Cell Line
;
Digoxin/*analogs & derivatives/chemistry/metabolism/*pharmacology/therapeutic use
;
Drosophila/cytology
;
Humans
;
Interleukin-17/biosynthesis/immunology
;
Mice
;
Nuclear Receptor Subfamily 1, Group F, Member 3/*antagonists &
;
inhibitors/metabolism
;
Th17 Cells/*cytology/*drug effects/immunology
;
Transcription, Genetic/drug effects/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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