Protective Role of Complement C3 Against Cytokine-Mediated β-Cell Apoptosis
Protective Role of Complement C3 Against Cytokine-Mediated β-Cell Apoptosis
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补体C3对细胞因子介导的β细胞凋亡的保护作用
DOI：
10.1210/en.2017-00104
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发表时间：
2017-08-01
期刊：
影响因子：
4.8
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Dos Santos, Reinaldo S.;Marroqui, Laura;Eizirik, Decio L.
1型糖尿病是一种慢性自身免疫性疾病，其特征在于胰岛炎症和促炎细胞因子和其他介质引起的β细胞破坏。基于对暴露于促炎细胞因子的人类胰岛的RNA测序和蛋白质-蛋白质相互作用分析，我们鉴定了补体C3作为细胞因子的一些作用的中心。促炎细胞因子白细胞介素-1 β加干扰素-γ增加啮齿动物和人类胰腺β细胞中的C3表达，并且通过组织学在糖尿病患者的胰岛中及其周围检测到C3。令人惊讶的是，C3沉默在基础条件下和暴露于细胞因子后都加剧了细胞凋亡，并且在细胞因子处理后增加了趋化因子表达。C3通过AKT激活和c-Jun N-末端激酶抑制发挥其促生存作用。外源性添加的C3还保护免受甜菜碱诱导的β细胞死亡，并部分挽救内源性C3抑制的有害作用。这些数据表明，局部产生的C3是胰腺β细胞在促炎攻击下的重要促生存机制。
Type 1 diabetes is a chronic autoimmune disease characterized by pancreatic islet inflammation and beta-cell destruction by proinflammatory cytokines and other mediators. Based on RNA sequencing and protein-protein interaction analyses of human islets exposed to proinflammatory cytokines, we identified complement C3 as a hub for some of the effects of cytokines. The proinflammatory cytokines interleukin-1 beta plus interferon-gamma increase C3 expression in rodent and human pancreatic beta-cells, and C3 is detected by histology in and around the islets of diabetic patients. Surprisingly, C3 silencing exacerbates apoptosis under both basal condition and following exposure to cytokines, and it increases chemokine expression upon cytokine treatment. C3 exerts its prosurvival effects via AKT activation and c-Jun N-terminal kinase inhibition. Exogenously added C3 also protects against cytokine-induced beta-cell death and partially rescues the deleterious effects of inhibition of endogenous C3. These data suggest that locally produced C3 is an important prosurvival mechanism in pancreatic beta-cells under a proinflammatory assault.