TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic ß-Cells.
Diabetes
; 64(11): 3808-17, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26239055
ABSTRACT
Pancreatic ß-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 ß-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human ß-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 IFNα and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early ß-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced ß-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic ß-cells via modulation of IFNα 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Apoptosis
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Diabetes Mellitus Tipo 1
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Células Secretoras de Insulina
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TYK2 Quinasa
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Inmunidad Innata
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article