dc.contributor.author | Dos Santos, Reinaldo S. | |
dc.contributor.author | Marroquí, Laura | |
dc.contributor.author | Velayos Gainza, Teresa | |
dc.contributor.author | Olazagoitia Garmendia, Ane | |
dc.contributor.author | Jauregi Miguel, Amaia | |
dc.contributor.author | Castellanos Rubio, Ainara | |
dc.contributor.author | Eizirik, Decio L. | |
dc.contributor.author | Castaño González, Luis Antonio ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.contributor.author | Santín Gómez, Izortze | |
dc.date.accessioned | 2024-02-06T14:46:38Z | |
dc.date.available | 2024-02-06T14:46:38Z | |
dc.date.issued | 2018-11-26 | |
dc.identifier.citation | Diabetologia 62(3) : 459-472 (2019) | es_ES |
dc.identifier.issn | 1432-0428 | |
dc.identifier.issn | 0012-186X | |
dc.identifier.uri | http://hdl.handle.net/10810/64679 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | 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 the NIH-
NIDDK-HIRN Consortium 1UC4DK104166-01, USA. TV and AJM were supported by
Predoctoral Fellowship grants from the UPV/EHU and the Basque Department of
Education, respectively. AOG is supported by a Predoctoral Fellowship Grant from the
Basque Department of Education. ACR is supported by an Ikerbasque Research Fellow
grant. LM was supported by a Fonds National de la Recherche Scientifique postdoctoral
fellowship. DLE has received funding from the Innovative Medicines Initiative 2 Joint
Undertaking under grant agreement No 115797 (INNODIA). This Joint Undertaking | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Springer | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/GA667191 | |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.subject | susceptibility gene | es_ES |
dc.subject | type 1 diabetes | |
dc.subject | pancreatic beta cell | |
dc.subject | inflammation | |
dc.subject | viral infection | |
dc.subject | type I IFNs | |
dc.subject | DEXI | |
dc.title | 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 | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2018, Springer-Verlag GmbH Germany, part of Springer Nature | es_ES |
dc.relation.publisherversion | https://doi.org/10.1007/s00125-018-4782-0 | |
dc.identifier.doi | 10.1007/s00125-018-4782-0 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |