Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity

Jun R. Huh, Monica W. L. Leung, Pengxiang Huang, Daniel A. Ryan, Michael R. Krout, Raghu R. V. Malapaka, Jonathan Chow, Nicolas Manel, Maria Ciofani, Sangwon V. Kim, Adolfo Cuesta, Fabio R. Santori, Juan J. Lafaille, H. Eric Xu, David Y. Gin, Fraydoon Rastinejad and Dan R. Littman ()
Additional contact information
Jun R. Huh: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Monica W. L. Leung: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Pengxiang Huang: Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road
Daniel A. Ryan: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Michael R. Krout: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Raghu R. V. Malapaka: Laboratory of Structural Sciences, Van Andel Research Institute
Jonathan Chow: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Nicolas Manel: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Maria Ciofani: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Sangwon V. Kim: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Adolfo Cuesta: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Fabio R. Santori: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Juan J. Lafaille: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
H. Eric Xu: Laboratory of Structural Sciences, Van Andel Research Institute
David Y. Gin: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Fraydoon Rastinejad: Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road
Dan R. Littman: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine

Nature, 2011, vol. 472, issue 7344, 486-490

Abstract: A new class of immunomodulator The nuclear receptors RORα and RORγt (retinoic acid receptor-related orphan receptors α and γt) are essential for the development of TH17 cells, the T-helper cells that produce interleukin-17. Two groups report the identification of RORγt inhibitors, compounds that could have potential in the treatment of autoimmune diseases. Huh et al. used a chemical screen in an insect-cell-based reporter system to identify the cardiac glycoside digoxin and various derivatives as inhibitors of the transcriptional activity of RORγt. Through this mechanism, these compounds block the differentiation of TH17 cells in mice, and inhibit interleukin-17 production in vitro in human T cells. Solt et al. describe a synthetic ligand, named SR1001, that functions as an inverse agonist for RORα and RORγt, and show that it blocks TH17 development in vitro and inhibits experimental encephalomyelitis in mice.

Date: 2011
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DOI: 10.1038/nature09978

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