Zhang Dongya, Wang Meiling, Shi Guoping, Pan Peng, Ji Jianjian, Li Pengfei
Key Laboratory of Inflammation and Immunoregulation, School of Medical and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Clinical Laboratory, Jiangsu Province Hospital of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Front Pharmacol. 2021 Jan 14;11:579298. doi: 10.3389/fphar.2020.579298. eCollection 2020.
It's well known that the mammalian target of rapamycin (mTOR) exerts a critical role in the regulator of immune cells and is associated with T cells dysfunction in patients with systemic lupus erythematosus (SLE). Antigen-induced T-cell proliferation via mTORC1 suppressed by Rapamycin has been used to improve SLE primarily. Previously it has showed that INK128, a highly potent, specific orally inhibitor of mTORC1 and mTORC2, significantly attenuates SLE in pristine-induced lupus mice. Herein we compared the cure effects of INK128 and rapamycin on lupus mice. We treated MRL/lpr mice with INK128 or rapamycin at 12 weeks-age. The effect of the two inhibitors on the lupus mice was determined by immunohistochemistry. The effect of the two inhibitors on T cell populations was investigated by flow cytometry. The mTOR signaling was measured by Western Blot. INK128 remarkably alleviated SLE by reducing splenomegaly, renal inflammation and damage, and resuming T-cell dysfunction. The more effective of INK128 on SLE than rapamycin. INK128 effectively suppressed mTORC1 and mTORC2 activity in T cells, but rapamycin just suppressed mTORC1 activity. Thus, our results show that INK128 is can effectively alleviate SLE and be used as one of the potential clinical therapeutic candidates for SLE.
众所周知，雷帕霉素的哺乳动物靶点（mTOR）在免疫细胞调节中发挥关键作用，且与系统性红斑狼疮（SLE）患者的T细胞功能障碍有关。通过雷帕霉素抑制mTORC1介导的抗原诱导的T细胞增殖已被主要用于改善SLE。此前已表明，INK128是一种高效、特异性的口服mTORC1和mTORC2抑制剂，可显著减轻初次诱导的狼疮小鼠的SLE症状。在此，我们比较了INK128和雷帕霉素对狼疮小鼠的治疗效果。我们在12周龄时用INK128或雷帕霉素治疗MRL/lpr小鼠。通过免疫组织化学确定两种抑制剂对狼疮小鼠的作用。通过流式细胞术研究两种抑制剂对T细胞群体的影响。通过蛋白质免疫印迹法检测mTOR信号传导。INK128通过减轻脾肿大、肾脏炎症和损伤以及恢复T细胞功能障碍，显著缓解了SLE。INK128对SLE的治疗效果比雷帕霉素更好。INK128有效抑制T细胞中的mTORC1和mTORC2活性，但雷帕霉素仅抑制mTORC1活性。因此，我们的结果表明，INK128可有效缓解SLE，并可作为SLE潜在的临床治疗候选药物之一。
