Wu Lina, Guo Feng, Wu Yang, Wang Qingzhu, Ma Xiaojun, Zhao Yanyan, Qin Guijun
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Microvasc Res. 2017 Jul;112:93-100. doi: 10.1016/j.mvr.2017.03.003. Epub 2017 Mar 7.
Diabetic retinopathy is a chronic, low-grade inflammatory disease. The present study aimed to investigate the effect of forkhead transcription factor O1 (FoxO1) expression on interleukin-1β (IL-1β)-induced autostimulation, both in vitro in human retina microvascular endothelial cells (HRMECs), and in vivo in retinas isolated from streptozotocin-induced diabetic rats. High-glucose (HG) and recombinant IL-1β treatment were both shown to increase the expression of FoxO1 and IL-1β in HRMECs in a dose-dependent manner. IL-1 receptor antagonist (IL-1RA) and mitogen-activated protein kinase (MAPK) inhibitors reduced IL-1β-induced expression of FoxO1 in HRMECs. Moreover, the increased expressions of FoxO1 and IL-1β in the retinas of diabetic rats were significantly decreased by intravitreal injection of lentiviral vector-mediated FoxO1 small-interfering RNA. Together, these results suggest that HG triggers IL-1β synthesis in HRMECs. The produced IL-1β induces increased FoxO1 expression, as well as interacts with the IL-1 receptor to activate MAPK signaling and thereby induces IL-1β autostimulation. The IL-1β-induced autostimulation can be inhibited by downregulation of FoxO1, accompanied by a reduction of inflammation. Together, these findings identify novel functions for FoxO1 and IL-1β in diabetic retinopathy.
糖尿病视网膜病变是一种慢性低度炎症性疾病。本研究旨在探讨叉头转录因子O1（FoxO1）表达对白细胞介素-1β（IL-1β）诱导的自身刺激的影响，包括在体外人视网膜微血管内皮细胞（HRMECs）中以及在从链脲佐菌素诱导的糖尿病大鼠分离的视网膜中进行体内研究。高糖（HG）和重组IL-1β处理均显示以剂量依赖性方式增加HRMECs中FoxO1和IL-1β的表达。IL-1受体拮抗剂（IL-1RA）和丝裂原活化蛋白激酶（MAPK）抑制剂降低了IL-1β诱导的HRMECs中FoxO1的表达。此外，通过玻璃体内注射慢病毒载体介导的FoxO1小干扰RNA，糖尿病大鼠视网膜中FoxO1和IL-1β的增加表达显著降低。总之，这些结果表明HG触发了HRMECs中IL-1β的合成。产生的IL-1β诱导FoxO1表达增加，并与IL-1受体相互作用以激活MAPK信号传导，从而诱导IL-1β自身刺激。下调FoxO1可抑制IL-1β诱导的自身刺激，并伴有炎症减轻。总之，这些发现确定了FoxO1和IL-1β在糖尿病视网膜病变中的新功能。
