Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2489 - 2496 |
| Number of pages | 8 |
| Journal | Diabetes |
| Volume | 64 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2015 |
Cite this
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Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets. / Stanley, William J; Litwak, Sara A; Quah, Hong Sheng; Tan, Sih Min; Kay, Thomas W H; Tiganis, Tony; De Haan-Klein, Judy Bettina; Thomas, Helen E; Gurzov, Esteban.
In: Diabetes, Vol. 64, No. 7, 2015, p. 2489 - 2496.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets
AU - Stanley, William J
AU - Litwak, Sara A
AU - Quah, Hong Sheng
AU - Tan, Sih Min
AU - Kay, Thomas W H
AU - Tiganis, Tony
AU - De Haan-Klein, Judy Bettina
AU - Thomas, Helen E
AU - Gurzov, Esteban
PY - 2015
Y1 - 2015
N2 - Type 1 diabetes (T1D) is the result of autoimmune assault against the insulin-producing pancreatic beta-cells, where chronic local inflammation (insulitis) leads to beta-cell destruction. T cells and macrophages infiltrate into islets early in T1D pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T cell invasion and activation. Cytokine signaling pathways are very tightly regulated by protein tyrosine phosphatases (PTPs) to prevent excessive activation. Here, we demonstrate that pancreata from non-obese diabetic (NOD) mice with islet infiltration have enhanced oxidation/inactivation of PTPs and STAT1 signaling when compared to NOD mice that do not have any insulitis. Inactivation of PTPs with sodium orthovanadate in human and rodent islets and beta-cells leads to increased activation of interferon signaling and chemokine production mediated by STAT1 phosphorylation. Furthermore, this exacerbated STAT1 activation induced cell death in islets was prevented by overexpression of the suppressor of cytokine signaling-1 or inactivation of the BH3-only protein Bim. Together our data provide a mechanism by which PTP inactivation induces signaling in pancreatic islets that results in increased expression of inflammatory genes and exacerbated insulitis.
AB - Type 1 diabetes (T1D) is the result of autoimmune assault against the insulin-producing pancreatic beta-cells, where chronic local inflammation (insulitis) leads to beta-cell destruction. T cells and macrophages infiltrate into islets early in T1D pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T cell invasion and activation. Cytokine signaling pathways are very tightly regulated by protein tyrosine phosphatases (PTPs) to prevent excessive activation. Here, we demonstrate that pancreata from non-obese diabetic (NOD) mice with islet infiltration have enhanced oxidation/inactivation of PTPs and STAT1 signaling when compared to NOD mice that do not have any insulitis. Inactivation of PTPs with sodium orthovanadate in human and rodent islets and beta-cells leads to increased activation of interferon signaling and chemokine production mediated by STAT1 phosphorylation. Furthermore, this exacerbated STAT1 activation induced cell death in islets was prevented by overexpression of the suppressor of cytokine signaling-1 or inactivation of the BH3-only protein Bim. Together our data provide a mechanism by which PTP inactivation induces signaling in pancreatic islets that results in increased expression of inflammatory genes and exacerbated insulitis.
UR - http://www.scopus.com/inward/record.url?scp=84962070981&partnerID=8YFLogxK
UR - http://diabetes.diabetesjournals.org/content/64/7/2489.full.pdf+html
U2 - 10.2337/db14-1575
DO - 10.2337/db14-1575
M3 - Article
VL - 64
SP - 2489
EP - 2496
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 7
ER -