Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets

William J Stanley, Sara A Litwak, Hong Sheng Quah, Sih Min Tan, Thomas W H Kay, Tony Tiganis, Judy Bettina De Haan-Klein, Helen E Thomas, Esteban Gurzov

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2489 - 2496
Number of pages8
Issue number7
Publication statusPublished - 2015

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