TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells
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Pancreatic β-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 β-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human β-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 β-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced β-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic β-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.
Original language | English |
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Journal | Diabetes |
Volume | 64 |
Issue number | 11 |
Pages (from-to) | 3808-17 |
Number of pages | 10 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - Nov 2015 |
- Apoptosis, Cell Line, Cell Survival, Chemokine CXCL10, Diabetes Mellitus, Type 1, Genes, MHC Class I, Genome-Wide Association Study, Humans, Immunity, Innate, Insulin-Secreting Cells, Interferon-alpha, Phosphorylation, Polymorphism, Single Nucleotide, TYK2 Kinase
Research areas
ID: 162645069