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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Insulin-Secreting Cells / metabolism*
  • Interferon-alpha / pharmacology*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Janus Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Real-Time Polymerase Chain Reaction
  • Sulfones / pharmacology

Substances

  • 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide
  • Histocompatibility Antigens Class I
  • INCB018424
  • Interferon-alpha
  • Janus Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Sulfones