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

Author

Listed:
  • 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
    Howard Hughes Medical 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
    Present address: Institut Curie, INSERM U932, 75005 Paris, France.)

  • 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
    Howard Hughes Medical 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
    Howard Hughes Medical Institute, New York University School of Medicine)

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.

Suggested Citation

  • 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., 2011. "Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity," Nature, Nature, vol. 472(7344), pages 486-490, April.
    • Handle: RePEc:nat:nature:v:472:y:2011:i:7344:d:10.1038_nature09978
    DOI: 10.1038/nature09978
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    Cited by:

    1. Wen-Lan Yang & Weinan Qiu & Ting Zhang & Kai Xu & Zi-Juan Gu & Yu Zhou & Heng-Ji Xu & Zhong-Zhou Yang & Bin Shen & Yong-Liang Zhao & Qi Zhou & Ying Yang & Wei Li & Peng-Yuan Yang & Yun-Gui Yang, 2023. "Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Joachim Hanna & Flavio Beke & Louise M. O’Brien & Chrysa Kapeni & Hung-Chang Chen & Valentina Carbonaro & Alexander B. Kim & Kamal Kishore & Timon E. Adolph & Mikkel-Ole Skjoedt & Karsten Skjoedt & Ma, 2022. "Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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