Alexandra Coomans de Brachène1, Reinaldo S Dos Santos2, Laura Marroqui2,3, Maikel L Colli2, Lorella Marselli4, Raghavendra G Mirmira5, Piero Marchetti4, Decio L Eizirik6. 1. ULB Center for Diabetes Research, Medical Faculty, Campus Erasme, Université Libre de Bruxelles, Route de Lennik, 808-CP618, B-1070, Brussels, Belgium. alcooman@ulb.ac.be. 2. ULB Center for Diabetes Research, Medical Faculty, Campus Erasme, Université Libre de Bruxelles, Route de Lennik, 808-CP618, B-1070, Brussels, Belgium. 3. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Institute of Bioengineering, Miguel Hernández University of Elche, Alicante, Spain. 4. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 5. Department of Pediatrics, Medicine, and Physiology, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, School of Medicine, Indianapolis, IN, USA. 6. ULB Center for Diabetes Research, Medical Faculty, Campus Erasme, Université Libre de Bruxelles, Route de Lennik, 808-CP618, B-1070, Brussels, Belgium. deizirik@ulb.ac.be.
Abstract
AIMS/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.
AIMS/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.
Entities:
Keywords:
IFN-α; JAK inhibitors; MHC class I; Pancreatic beta cells; Pancreatic islets; Type 1 diabetes
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