title: TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells.
abstract: 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.
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium lmarroqu@ulb.ac.be.
authors.forename: Laura
authors.initials: L
authors.lastname: Marroqui
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Reinaldo Sousa
authors.initials: RS
authors.lastname: Dos Santos
authors.affiliation: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Fløyel
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Grieco
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium Endocrinology and Diabetes Research Group, BioCruces Health Research Institute and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Barakaldo, Spain.
authors.forename: Izortze
authors.initials: I
authors.lastname: Santin
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Op de Beeck
authors.affiliation: Department of Clinical and Experimental Medicine, Pancreatic Islet Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Clinical and Experimental Medicine, Pancreatic Islet Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005805:Genes, MHC Class I / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D053634:TYK2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D016898:Interferon-alpha; D053634:TYK2 Kinase; C070139:TYK2 protein, human