期刊
DIABETES
卷 64, 期 11, 页码 3808-3817出版社
AMER DIABETES ASSOC
DOI: 10.2337/db15-0362
关键词
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资金
- Fonds National de la Recherche Scientifique (FNRS), Belgium
- Communaute Francaise de Belgique-Actions de Recherche Concertees (ARC)
- European Union
- FNRS postdoctoral fellowship
- Conselho Nacional de Desenvolvimento Cientifico e tecnologico (CNPq), Brazil
- European Foundation for the Study of Diabetes (EFSD/JDRF/NN)
- Education Department of the Basque Country
Pancreatic beta-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic beta-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human beta-cells exposed to polyinosinic-polycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFN alpha and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early beta-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced beta-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic beta-cells via modulation of IFN alpha signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.
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