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Diabetologia. 2018 Mar;61(3):636-640. doi: 10.1007/s00125-017-4536-4. Epub 2018 Jan 5.

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells.

Author information

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.

KEYWORDS:

IFN-α; JAK inhibitors; MHC class I; Pancreatic beta cells; Pancreatic islets; Type 1 diabetes

PMID:
29305625
PMCID:
PMC6241216
DOI:
10.1007/s00125-017-4536-4
[Indexed for MEDLINE]
Free PMC Article

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