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

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.

• Authors: Alexandra Coomans de Brachène, Reinaldo S Dos Santos, Laura Marroqui, Maikel L Colli, Lorella Marselli, Raghavendra G Mirmira, Piero Marchetti, Decio L Eizirik
• Journal: Diabetologia (Diabetologia) Vol. 61 Issue 3 Pg. 636-640 (03 2018) ISSN: 1432-0428 [Electronic] Germany
• PMID: 29305625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide
• Histocompatibility Antigens Class I
• Interferon-alpha
• Janus Kinase Inhibitors
• Nitriles
• Pyrazoles
• Pyrimidines
• Sulfones
• ruxolitinib

Topics

• Blotting, Western
• Cell Line
• Diabetes Mellitus, Type 1 (metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Insulin-Secreting Cells (drug effects, metabolism)
• Interferon-alpha (pharmacology)
• Islets of Langerhans (cytology, drug effects)
• Janus Kinase Inhibitors (pharmacology)
• Nitriles
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Real-Time Polymerase Chain Reaction
• Sulfones (pharmacology)