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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01460

Digoxin, an overlooked agonist of RORγ/RORγT

  • 1Institute for Medical Biology (PAN), Poland
  • 2University of Łódź, Poland

Digoxin was one of the first identified RORγT receptor inverse agonists inhibiting the differentiation of Th17 cells. However, this compound exhibits inhibitory activity at relatively high concentrations that mediate cytotoxic effects. We previously identified several cardenolides that are structurally similar to digoxin that were able to induce RORγ/RORγT-dependent transcription. These observations encouraged us to reanalyze the effects of digoxin on RORγ/RORγT-dependent transcription at low, noncytotoxic concentrations. Digoxin induced RORγ/RORγT-dependent transcription in HepG2 and Th17 cells. Furthermore, analysis of the transcriptomes of Th17 cells cultured in the presence of digoxin revealed the induction of the expression of numerous Th17-specific genes, including IL17A/F, IL21, IL22, IL23R, CCR4 and CCR6. Thus, our study, which includes data obtained from intact cells, indicates that digoxin, similar to other cardenolides, is a potent RORγ/RORγT receptor activator and that its structure may serve as a starting point for the design of dedicated molecules that can be used in the development of adoptive cell therapy.

Keywords: RORgamma, RORC, agonist, Digoxin, molecular docking, Th17

Received: 15 Oct 2018; Accepted: 29 Nov 2018.

Edited by:

Stefania Tacconelli, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy

Reviewed by:

Georgios Paschos, University of Pennsylvania, United States
Soon Yew Tang, University of Pennsylvania, United States  

Copyright: © 2018 Karaś, Sałkowska, Sobalska-Kwapis, Drzewiecka, Strapagiel, Dastych, Bachorz and Ratajewski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Marcin Ratajewski, Institute for Medical Biology (PAN), Łódź, 93-232, Łódź, Poland, mratajewski@cbm.pan.pl