Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

Diabetologia. 2017 Apr;60(4):656-667. doi: 10.1007/s00125-016-4201-3. Epub 2017 Jan 6.


Aims/hypothesis: Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis.

Methods: IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.

Results: IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis.

Conclusions/interpretation: The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

Keywords: Apoptosis; ER stress; IFNα; MHC class I; Pancreatic beta cells; Pancreatic islets; Type 1 diabetes; Type I IFN signalling.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Interferon-alpha / pharmacology*
  • Interleukin-1beta / pharmacology
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Histocompatibility Antigens Class I
  • Interferon-alpha
  • Interleukin-1beta
  • Transcription Factors