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Diabetologia. 2019 Mar;62(3):459-472. doi: 10.1007/s00125-018-4782-0. Epub 2018 Nov 26.

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.

Author information

1
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium.
2
Instituto de Biología Molecular y Celular (IBMC), and Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain.
3
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
4
Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
5
Department of Pediatrics, University of the Basque Country, Leioa, Spain.
6
Department of Genetics, Physical Anthropology and Animal Fisiology, University of the Basque Country, Leioa, Spain.
7
CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
8
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. izortze.santin@ehu.eus.
9
Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. izortze.santin@ehu.eus.
10
CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. izortze.santin@ehu.eus.
11
Department of Biochemistry and Molecular Biology, University of the Basque Country, Barrio Sarriena, S/N, 48940, Leioa, Bizkaia, Spain. izortze.santin@ehu.eus.

Abstract

AIMS/HYPOTHESIS:

The initial stages of type 1 diabetes are characterised 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 is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore 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. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.

RESULTS:

DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.

CONCLUSIONS/INTERPRETATION:

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 responses in beta cells. Moreover, our results provide initial information on the function of DEXI.

KEYWORDS:

DEXI; Inflammation; Pancreatic beta cell; Susceptibility gene; Type 1 diabetes; Type I IFNs; Viral infection

PMID:
30478640
DOI:
10.1007/s00125-018-4782-0

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