RT Journal Article SR Electronic T1 TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells JF Diabetes JO Diabetes FD American Diabetes Association SP 3808 OP 3817 DO 10.2337/db15-0362 VO 64 IS 11 A1 Marroqui, Laura A1 Dos Santos, Reinaldo Sousa A1 Fløyel, Tina A1 Grieco, Fabio A. A1 Santin, Izortze A1 Op de beeck, Anne A1 Marselli, Lorella A1 Marchetti, Piero A1 Pociot, Flemming A1 Eizirik, Decio L. YR 2015 UL http://diabetes.diabetesjournals.org/content/64/11/3808.abstract AB 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.