Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets.
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 of inflammatory genes and exacerbated insulitis.
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
William J
WJ
Stanley
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
Sara A
SA
Litwak
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
Hong Sheng
HS
Quah
Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Sih Min
SM
Tan
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
Thomas W H
TW
Kay
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
Tony
T
Tiganis
Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Judy B
JB
de Haan
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
Helen E
HE
Thomas
St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia egurzov@svi.edu.au.
Esteban N
EN
Gurzov
D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D017027:Protein Tyrosine Phosphatases