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Double-stranded RNA induces pancreatic beta cell apoptosis by activation of the TLR3 and IRF-3 pathways
Objective: Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta cell death.
Research Design and Methods: Primary rat beta cells and islet cells from wild type, Toll-like receptor 3 (TLR3), type I interferon receptor (IFNAR1) or interferon regulatory factor 3 (IRF-3) knockout mice were exposed to external dsRNA (polyinosinic polycytidylic acid; PICex) or were transfected with dsRNA (PICin).
Results: TLR3 signaling mediated PICex-induced NF-B and IRF-3 activation and beta cell apoptosis. PICin activated NF-B and IRF-3 in a TLR3-independent manner, induced eIF2 phosphorylation and triggered a massive production of IFN-β. This contributed to beta cell death as islet cells from IFNAR1-/- or IRF-3-/- mice were protected against PICin-induced apoptosis.
Conclusions: External and internal dsRNA trigger beta cell apoptosis via respectively the TLR3 pathway or IRF-3 signaling. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.
http://diabetes.diabetesjournals ... bstract/db07-0844v1
作者单位
1Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
2Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM- Université de la Mediterranée, Marseille, France
3Institute of Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
4Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Leuven, Belgium
5Department for Molecular Biomedical Research, VIB - Ghent University, Ghent, Belgium
目的:病毒感染参与1型糖尿病的发病。病毒或病毒产物——例如双链RNA(dsRNA),影响胰岛β细胞存活并启动自身免疫,其机制不明。最近,我们研究了下游双链RNA效应物及其介质诱导β细胞死亡的机制。
实验设计和方法:原代β细胞&胰岛细胞来自于野生型大鼠和Toll样受体3、I型干扰素受体(IFNAR1)或干扰素调节因子-3 (IRF-3)基因敲除小鼠,行外源性双链RNA(外源性聚肌胞苷酸; PICex)暴露或转染双链RNA(PICin)干预。
结果:TLR3介导外源性聚肌胞苷酸(PICex)诱导的核因子-B、干扰素调节因子-3活化和β细胞凋亡。而PICin诱导核因子-B、干扰素调节因子-3活化是非TLR3依赖性的,它是通过诱导真核起始因子2磷酸化并触发干扰素β大量合成,促进了β细胞的死亡。但当胰岛细胞来源于I型干扰素受体(IFNAR1)或干扰素调节因子-3 (IRF-3)基因敲除小鼠时,便免于PICin诱导凋亡的影响。
结论:外源性和内源性双链RNA触发β细胞凋亡,是分别通过TLR3途径、IRF-3信号通路实现。PICin介导的细胞凋亡依赖I型干扰素自分泌效应。
http://diabetes.diabetesjournals ... bstract/db07-0844v1
作者单位
1.Laboratory of Experimental Medicine,布鲁塞尔自由大学,布鲁塞尔,比利时
2.Centre d'Immunologie de Marseille-Luminy,法国科学院-国家健康保健研究所-艾克斯-马赛二大,马赛,法国
3.Institute of Medical Immunology,布鲁塞尔自由大学,布鲁塞尔,比利时
4.Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N,鲁汶大学,鲁汶,比利时
5.Department for Molecular Biomedical Research,法兰德斯大学校际生物科技研究所-肯特大学,肯特,比利时
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