Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes
Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes
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DOI：
10.1007/s00125-016-4201-3
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发表时间：
2017-04-01
期刊：
影响因子：
8.2
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Marroqui, Laura;Dos Santos, Reinaldo S.;Eizirik, Decio L.
目的/假设早期1型糖尿病患者胰岛的三个特征是HLA I类的过度表达、内质网应激和β细胞凋亡。这些现象的中介仍有待确定。I型干扰素IFN α在1型糖尿病患者胰岛中表达并介导HLA I型过表达。我们目前评估了IFN α诱导人β细胞中HLA I类表达的机制，并确定该细胞因子是否有助于内质网应激和细胞凋亡。方法采用RT-PCR、western blot、免疫荧光和核染色等方法观察IFN α诱导的炎症反应、内质网应激和细胞凋亡，并用小干扰rna抑制I型干扰素信号传导相关蛋白。所有实验均在人胰岛或人endoc - β H1细胞中进行。结果IFN α通过激活候选基因TYK2、转录因子信号转导和转录激活因子2和IFN调节因子9，上调人β细胞HLA I类、炎症和内质网应激标志物。此外，它与IL-1 β协同作用，诱导β细胞凋亡。结论/解释IFNa诱导的先天免疫效应可能诱导和放大针对人β细胞的适应性免疫反应，表明IFN α在糖尿病早期阶段发挥核心作用。
Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFN alpha is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFN alpha-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis.Methods IFN alpha-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-beta H1 cells.Results IFN alpha upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1 beta to induce beta cell apoptosis.Conclusions/interpretation The innate immune effects induced by IFNa may induce and amplify the adaptive immune response against human beta cells, indicating that IFN alpha has a central role in the early phases of diabetes.