de Brachène, Alexandra CoomansDos Santos, Reinaldo SousaMarroqui, LauraColli, Maikel L.Marselli, LorellaMirmira, Raghavendra G.Marchetti, PieroEizirik, Decio L.2018-10-032018-10-032018-04de Brachène, A. C., Santos, R. S. D., Marroqui, L., Colli, M. L., Marselli, L., Mirmira, R. G., … Eizirik, D. L. (2018). IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells. Diabetologia, 61(3), 636–640. https://doi.org/10.1007/s00125-017-4536-4https://hdl.handle.net/1805/17439Aims/hypothesis IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition. Methods IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot. Results IFN-α-induced expression of inflammatory and ER stress markers returned to baseline after 24–48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-α, prevented MHC class I overexpression, but when added 24 h after IFN-α exposure these inhibitors failed to accelerate MHC class I return to baseline. Conclusions/interpretation IFN-α mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-α-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-α inhibitors might need to be used at very early stages of the disease to be effective.enPublisher PolicyIFN-αJAK inhibitorsMHC class IArticle