Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets

Diabetes
William J StanleyE N Gurzov

Abstract

Type 1 diabetes (T1D) is the result of an autoimmune assault against the insulin-producing pancreatic β-cells, where chronic local inflammation (insulitis) leads to β-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 NOD mice with islet infiltration have enhanced oxidation/inactivation of PTPs and STAT1 signaling compared with NOD mice that do not have insulitis. Inactivation of PTPs with sodium orthovanadate in human and rodent islets and β-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 o...Continue Reading

References

Jun 1, 1997·European Journal of Clinical Investigation·S R MaxwellA H Barnett
Jan 1, 1997·Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association·B RocićZ Metelko
Mar 20, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·K SukM S Lee
Apr 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mark M W ChongHelen E Thomas
Dec 14, 2004·Methods : a Companion to Methods in Enzymology·Camilla PerssonTobias Sjöblom
Feb 9, 2005·Annals of the New York Academy of Sciences·Shiva Reddy, Joshua Bradley
Jun 10, 2005·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Hirohito IchiiCamillo Ricordi
Apr 1, 2006·International Immunology·Mark D McKenzieHelen E Thomas
Jan 24, 2007·The Biochemical Journal·Tony Tiganis, Anton M Bennett
May 17, 2008·Biochemical Society Transactions·Sigurd Lenzen
Apr 9, 2009·Nature Reviews. Endocrinology·Décio L EizirikFernanda Ortis
May 12, 2009·Nature Genetics·Jeffrey C BarrettUNKNOWN Type 1 Diabetes Genetics Consortium
Oct 29, 2010·The Journal of Biological Chemistry·Fabrice MooreDecio L Eizirik
Apr 13, 2011·Trends in Cell Biology·Esteban N Gurzov, Decio L Eizirik
May 4, 2011·Cell Transplantation·Peter D CampbellHelen E Thomas
Aug 23, 2011·Journal of Biochemistry·Arne OstmanFrank-D Böhmer
Apr 17, 2012·Molecular and Cellular Endocrinology·Jessica R WeaverDavid A Taylor-Fishwick
Nov 30, 2014·Trends in Endocrinology and Metabolism : TEM·Esteban N GurzovHelen E Thomas

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Citations

Mar 26, 2016·Molecular Aspects of Medicine·Giuseppe MaulucciShlomo Sasson
Oct 19, 2017·Antioxidants & Redox Signaling·Ashley R Burg, Hubert M Tse
Nov 22, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ashley R BurgHubert M Tse
Aug 23, 2017·Journal of Molecular Endocrinology·William J StanleyEsteban N Gurzov
Mar 15, 2016·The FEBS Journal·Esteban N GurzovDaniel J Gough
Oct 17, 2017·Biomacromolecules·Emily H PilkingtonPu Chun Ke
Oct 16, 2021·Molecular Pharmaceutics·Maria ErikssonEsteban N Gurzov

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