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

Alexandra Coomans de Brachène, Reinaldo S. Dos Santos, Laura Marroqui, Maikel L. Colli, Lorella Marselli, Raghu Mirmira, Piero Marchetti, Decio L. Eizirik

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-5
Number of pages5
JournalDiabetologia
DOIs
StateAccepted/In press - Jan 5 2018

Fingerprint

Insulin-Secreting Cells
Janus Kinases
Endoplasmic Reticulum Stress
Type 1 Diabetes Mellitus
Cytokines
Inflammation
Antigen Presentation
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Histology
Flow Cytometry
Western Blotting
Proteins

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Coomans de Brachène, A., Dos Santos, R. S., Marroqui, L., Colli, M. L., Marselli, L., Mirmira, R., ... Eizirik, D. L. (Accepted/In press). IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells. Diabetologia, 1-5. https://doi.org/10.1007/s00125-017-4536-4

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells. / Coomans de Brachène, Alexandra; Dos Santos, Reinaldo S.; Marroqui, Laura; Colli, Maikel L.; Marselli, Lorella; Mirmira, Raghu; Marchetti, Piero; Eizirik, Decio L.

In: Diabetologia, 05.01.2018, p. 1-5.

Research output: Contribution to journalArticle

Coomans de Brachène, A, Dos Santos, RS, Marroqui, L, Colli, ML, Marselli, L, Mirmira, R, Marchetti, P & Eizirik, DL 2018, 'IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells', Diabetologia, pp. 1-5. https://doi.org/10.1007/s00125-017-4536-4
Coomans de Brachène, Alexandra ; Dos Santos, Reinaldo S. ; Marroqui, Laura ; Colli, Maikel L. ; Marselli, Lorella ; Mirmira, Raghu ; Marchetti, Piero ; Eizirik, Decio L. / IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells. In: Diabetologia. 2018 ; pp. 1-5.
@article{ff46ca732eaf45f3b87dcfc96a16296a,
title = "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.",
keywords = "IFN-α, JAK inhibitors, MHC class I, Pancreatic beta cells, Pancreatic islets, Type 1 diabetes",
author = "{Coomans de Brach{\`e}ne}, Alexandra and {Dos Santos}, {Reinaldo S.} and Laura Marroqui and Colli, {Maikel L.} and Lorella Marselli and Raghu Mirmira and Piero Marchetti and Eizirik, {Decio L.}",
year = "2018",
month = "1",
day = "5",
doi = "10.1007/s00125-017-4536-4",
language = "English (US)",
pages = "1--5",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

AU - Coomans de Brachène, Alexandra

AU - Dos Santos, Reinaldo S.

AU - Marroqui, Laura

AU - Colli, Maikel L.

AU - Marselli, Lorella

AU - Mirmira, Raghu

AU - Marchetti, Piero

AU - Eizirik, Decio L.

PY - 2018/1/5

Y1 - 2018/1/5

N2 - 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.

AB - 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.

KW - IFN-α

KW - JAK inhibitors

KW - MHC class I

KW - Pancreatic beta cells

KW - Pancreatic islets

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85040035898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040035898&partnerID=8YFLogxK

U2 - 10.1007/s00125-017-4536-4

DO - 10.1007/s00125-017-4536-4

M3 - Article

SP - 1

EP - 5

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

ER -