Dos Santos Reinaldo S, Marroqui Laura, Grieco Fabio A, Marselli Lorella, Suleiman Mara, Henz Stefan R, Marchetti Piero, Wernersson Rasmus, Eizirik Decio L
Université Libre de Bruxelles Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
Endocrinology. 2017 Aug 1;158(8):2503-2521. doi: 10.1210/en.2017-00104.
Type 1 diabetes is a chronic autoimmune disease characterized by pancreatic islet inflammation and β-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-1β plus interferon-γ increase C3 expression in rodent and human pancreatic β-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 β-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 β-cells under a proinflammatory assault.
1型糖尿病是一种慢性自身免疫性疾病，其特征是胰岛炎症以及促炎细胞因子和其他介质对β细胞的破坏。基于对暴露于促炎细胞因子的人胰岛进行的RNA测序和蛋白质-蛋白质相互作用分析，我们确定补体C3是细胞因子某些作用的枢纽。促炎细胞因子白细胞介素-1β加干扰素-γ可增加啮齿动物和人胰腺β细胞中的C3表达，并且在糖尿病患者胰岛内及周围通过组织学检测到C3。令人惊讶的是，C3沉默在基础条件下以及暴露于细胞因子后都会加剧细胞凋亡，并且在细胞因子处理后会增加趋化因子表达。C3通过AKT激活和c-Jun氨基末端激酶抑制发挥其促生存作用。外源性添加的C3还可防止细胞因子诱导的β细胞死亡，并部分挽救抑制内源性C3的有害作用。这些数据表明，在促炎攻击下，局部产生的C3是胰腺β细胞中一种重要的促生存机制。
