دورية أكاديمية
DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway
| العنوان: | DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway |
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| المؤلفون: | Dos Santos, Reinaldo S., Marroquí, Laura, Velayos Gainza, Teresa, Olazagoitia Garmendia, Ane, Jauregi Miguel, Amaia, Castellanos Rubio, Ainara, Eizirik, Decio L., Castaño González, Luis Antonio, Santín Gómez, Izortze |
| المساهمون: | European Commission |
| بيانات النشر: | Springer |
| سنة النشر: | 2018 |
| المجموعة: | ADDI: Repositorio Institucional de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU - Basque Country University) |
| مصطلحات موضوعية: | susceptibility gene, type 1 diabetes, pancreatic beta cell, inflammation, viral infection, type I IFNs, DEXI |
| الوصف: | Aims/hypothesis: The initial stages of type 1 diabetes are characterized by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A has been considered the etiologic gene in the region. However, recent gene expression analysis indicates that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI. We presently evaluated the role of DEXI in beta cell responses to “danger signals” and determined the mechanisms involved. Methods: Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Viral double-stranded RNA-driven beta cell inflammation and apoptosis were evaluated by RT-PCR, western blot and luciferase assays. Results: DEXI-silenced beta cells exposed to double-stranded RNA (PIC; a by-product of viral replication) showed reduced STAT1 activation and lower production of pro-inflammatory chemokines that was preceded by a reduction in IFN expression. Exposure to PIC increased chromatin-bound DEXI and IFN promoter activity. This effect on IFN promoter was inhibited in DEXI-silenced betacells, suggesting that DEXI is implicated in the regulation of IFNtranscription. In a mirror image of knockdown experiments, DEXI overexpression led to increased STAT1 and pro-inflammatory chemokine expression. Conclusions: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune response in beta cells. Moreover, our results provide initial information on the function of DEXI. ; This work was supported by a Research Project Grant from the Basque Department of Health (2015111068), a Research Grant from Fundación de la Sociedad Española de Diabetes (FSED), the Horizon 2020 Program T2Dsystems (GA667191) and ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1432-0428 0012-186X |
| العلاقة: | info:eu-repo/grantAgreement/EC/H2020/GA667191; https://doi.org/10.1007/s00125-018-4782-0Test; Diabetologia 62(3) : 459-472 (2019); http://hdl.handle.net/10810/64679Test |
| DOI: | 10.1007/s00125-018-4782-0 |
| الإتاحة: | https://doi.org/10.1007/s00125-018-4782-0Test http://hdl.handle.net/10810/64679Test |
| حقوق: | info:eu-repo/semantics/openAccess ; © 2018, Springer-Verlag GmbH Germany, part of Springer Nature |
| رقم الانضمام: | edsbas.278D660 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14320428 0012186X |
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| DOI: | 10.1007/s00125-018-4782-0 |