par Marroquí, Laura 
;Dos Santos, Reinaldo Sousa;Fløyel, Tina;Grieco, Fabio Arturo ;Santin Gomez, Izortze ;Op De Beeck, Anne ;Marselli, Lorella;Marchetti, Piero;Pociot, Flemming Michael;Eizirik, Decio L.
Référence Diabetes (New York, N.Y.), 64, 11, page (3808-3817)
Publication Publié, 2015-11
;Dos Santos, Reinaldo Sousa;Fløyel, Tina;Grieco, Fabio Arturo ;Santin Gomez, Izortze ;Op De Beeck, Anne ;Marselli, Lorella;Marchetti, Piero;Pociot, Flemming Michael;Eizirik, Decio L. Référence Diabetes (New York, N.Y.), 64, 11, page (3808-3817)
Publication Publié, 2015-11
Article révisé par les pairs
| Résumé : | 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. |
