mTOR inhibitor INK128 attenuates dextran sodium sulfate-induced colitis by promotion of MDSCs on Treg cell expansion
mTOR inhibitor INK128 attenuates dextran sodium sulfate-induced colitis by promotion of MDSCs on Treg cell expansion
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DOI：
10.1002/jcp.27032
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
--
作者：
Shi, Guoping;Li, Dan;Hou, Yayi
越来越多的证据表明，哺乳动物雷帕霉素靶蛋白（mTOR）途径和骨髓源性抑制细胞（MDSC）参与炎症性肠道疾病（IBD）的发病机制。INK 128是一种新型mTOR激酶抑制剂，正在临床开发中。然而，MDSC和INK 128在IBD中的确切作用尚不清楚。在这里，我们表明INK 128治疗增强了小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎的抵抗力，并抑制了MDSC向巨噬细胞的分化。此外，在INK 128治疗的结肠炎小鼠中，干扰素（IFN）-α水平升高。当在体外用IFN-α刺激时，MDSC显示出上级的免疫抑制活性。值得注意的是，在INK 128治疗的结肠炎小鼠中，调节性T细胞（TcR）增加，但Th 1细胞减少。这些结果表明，mTOR抑制剂INK 128通过MDSC促进的Treg扩增减弱DSS诱导的结肠炎。我们的工作提供了一个新的证据，即INK 128有可能通过调节MDSC以及维持Treg扩增而成为DSS诱导的结肠炎的治疗药物。
Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in pathogenesis of inflammatory bowel diseases (IBDs). INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in IBD are unclear. Here, we showed that the INK128 treatment enhanced the resistance of mice to dextran sodium sulfate (DSS)-induced colitis and inhibited the differentiation of MDSCs into macrophages. Moreover, interferon (IFN)-alpha level was elevated in INK128-treated colitis mice. When stimulated with IFN-alpha in vitro, MDSCs showed a superior immunosuppression activity. Of note, the regulatory T cells (Tregs) increased but Th1 cells decreased in INK128-treated colitis mice. These results indicate that mTOR inhibitor INK128 attenuates DSS-induced colitis via Treg expansion promoted by MDSCs. Our work provides a new evidence that INK128 is potential to be a therapeutic drug on DSS-induced colitis via regulating MDSCs as well as maintaining Treg expansion.