Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse

Malin Flodström-Tullberg, Deepak Yadav, Robert Hägerkvist, Devin Tsai, Patrick Secrest, Alexandr Stotland, Nora E Sarvetnick

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of β-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in β-cell death. We investigated whether β-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring β-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) litter-mates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing β-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target β-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by β-cells can represent a promising strategy to prevent type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)2696-2700
Number of pages5
JournalDiabetes
Volume52
Issue number11
DOIs
StatePublished - Nov 1 2003

Fingerprint

Inbred NOD Mouse
Cytokines
Type 1 Diabetes Mellitus
Transgenic Mice
Janus Kinase 1
Lymphocytes
Transducers
Blood Glucose
Pancreas
Cell Death
Maintenance
Phosphorylation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Flodström-Tullberg, M., Yadav, D., Hägerkvist, R., Tsai, D., Secrest, P., Stotland, A., & Sarvetnick, N. E. (2003). Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse. Diabetes, 52(11), 2696-2700. https://doi.org/10.2337/diabetes.52.11.2696

Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse. / Flodström-Tullberg, Malin; Yadav, Deepak; Hägerkvist, Robert; Tsai, Devin; Secrest, Patrick; Stotland, Alexandr; Sarvetnick, Nora E.

In: Diabetes, Vol. 52, No. 11, 01.11.2003, p. 2696-2700.

Research output: Contribution to journalArticle

Flodström-Tullberg, M, Yadav, D, Hägerkvist, R, Tsai, D, Secrest, P, Stotland, A & Sarvetnick, NE 2003, 'Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse', Diabetes, vol. 52, no. 11, pp. 2696-2700. https://doi.org/10.2337/diabetes.52.11.2696
Flodström-Tullberg M, Yadav D, Hägerkvist R, Tsai D, Secrest P, Stotland A et al. Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse. Diabetes. 2003 Nov 1;52(11):2696-2700. https://doi.org/10.2337/diabetes.52.11.2696
Flodström-Tullberg, Malin ; Yadav, Deepak ; Hägerkvist, Robert ; Tsai, Devin ; Secrest, Patrick ; Stotland, Alexandr ; Sarvetnick, Nora E. / Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse. In: Diabetes. 2003 ; Vol. 52, No. 11. pp. 2696-2700.
@article{1b11ca8d384444aaa79b5e23795185bb,
title = "Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse",
abstract = "Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of β-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in β-cell death. We investigated whether β-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring β-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) litter-mates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing β-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target β-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by β-cells can represent a promising strategy to prevent type 1 diabetes.",
author = "Malin Flodstr{\"o}m-Tullberg and Deepak Yadav and Robert H{\"a}gerkvist and Devin Tsai and Patrick Secrest and Alexandr Stotland and Sarvetnick, {Nora E}",
year = "2003",
month = "11",
day = "1",
doi = "10.2337/diabetes.52.11.2696",
language = "English (US)",
volume = "52",
pages = "2696--2700",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",

}

TY - JOUR

T1 - Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse

AU - Flodström-Tullberg, Malin

AU - Yadav, Deepak

AU - Hägerkvist, Robert

AU - Tsai, Devin

AU - Secrest, Patrick

AU - Stotland, Alexandr

AU - Sarvetnick, Nora E

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of β-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in β-cell death. We investigated whether β-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring β-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) litter-mates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing β-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target β-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by β-cells can represent a promising strategy to prevent type 1 diabetes.

AB - Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of β-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in β-cell death. We investigated whether β-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring β-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) litter-mates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1-expressing β-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target β-cell. Importantly, given that the SOCS-1-expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by β-cells can represent a promising strategy to prevent type 1 diabetes.

UR - http://www.scopus.com/inward/record.url?scp=0242268904&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0242268904&partnerID=8YFLogxK

U2 - 10.2337/diabetes.52.11.2696

DO - 10.2337/diabetes.52.11.2696

M3 - Article

VL - 52

SP - 2696

EP - 2700

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -