Karaś Kaja, Sałkowska Anna, Sobalska-Kwapis Marta, Walczak-Drzewiecka Aurelia, Strapagiel Dominik, Dastych Jarosław, Bachorz Rafał A, Ratajewski Marcin
Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland.
Biobank Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
Front Pharmacol. 2019 Jan 7;9:1460. doi: 10.3389/fphar.2018.01460. eCollection 2018.
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 (ACT).
地高辛是最早被鉴定出的抑制Th17细胞分化的RORγT受体反向激动剂之一。然而，该化合物在介导细胞毒性作用的相对高浓度下表现出抑制活性。我们之前鉴定了几种结构与地高辛相似的强心甾，它们能够诱导RORγ/RORγT依赖性转录。这些观察结果促使我们重新分析地高辛在低非细胞毒性浓度下对RORγ/RORγT依赖性转录的影响。地高辛在HepG2细胞和Th17细胞中诱导RORγ/RORγT依赖性转录。此外，对在存在地高辛的情况下培养的Th17细胞转录组的分析揭示了许多Th17特异性基因表达的诱导，包括IL17A/F、IL21、IL22、IL23R、CCR4和CCR6。因此，我们的研究（包括从完整细胞获得的数据）表明，地高辛与其他强心甾相似，是一种有效的RORγ/RORγT受体激活剂，其结构可作为设计用于过继性细胞疗法（ACT）开发的专用分子的起点。
