双链RNA通过活化TLR3 ＆IRF-3途径诱导胰岛β细胞凋亡
Double-stranded RNA induces pancreatic beta cell apoptosis by activation of the TLR3 and IRF-3 pathwaysObjective: 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.org/cgi/content/abstract/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.org/cgi/content/abstract/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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