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.
Nature. 2011 Apr 28;472(7344):486-90. doi: 10.1038/nature09978. Epub 2011 Mar 27.
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 RORγt, 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 RORγt 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 RORγt 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 RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.
表达白细胞介素-17（T(H)17 细胞）的 CD4(+)辅助性 T 淋巴细胞在自身免疫的小鼠模型中起着关键作用，越来越多的证据表明它们也会影响人类的炎症过程。人类的全基因组关联研究将参与 T(H)17 细胞分化和功能的基因与克罗恩病、类风湿关节炎和银屑病的易感性联系起来。因此，T(H)17 细胞分化的途径，也许还有具有类似效应功能的相关先天淋巴细胞，是治疗应用的一个有吸引力的目标。小鼠和人类的 T(H)17 细胞通过表达维甲酸受体相关孤儿核受体 RORγt 来区分，该受体对于诱导 IL-17 转录和在小鼠中表现出 T(H)17 依赖性自身免疫疾病是必需的。通过使用昆虫细胞报告系统进行化学筛选，我们发现地高辛是 RORγt 转录活性的特异性抑制剂。地高辛抑制小鼠 T(H)17 细胞分化，而不影响其他 T 细胞谱系的分化，并且在延迟小鼠自身免疫疾病的发病和减轻其严重程度方面有效。在高浓度下，地高辛对人类细胞有毒，但非毒性合成衍生物 20,22-二氢地高辛-21,23-二醇和地高辛-21-水杨醛特异性抑制人 CD4(+)T 细胞中 IL-17 的诱导。使用这些小分子化合物，我们证明 RORγt 对于维持小鼠和人类效应 T 细胞中 IL-17 的表达是重要的。这些数据表明，地高辛的衍生物可作为开发靶向 RORγt 的治疗剂的化学模板，这些治疗剂可减弱炎症性淋巴细胞功能和自身免疫性疾病。
