Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β are released in the islet during the autoimmune assault and signal in β-cells through phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate phosphorylative signalling and are associated with the development of T1D. Here, we observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese diabetic (NOD) mice. To clarify the role of these PTPs in β-cells/islets, we took advantage of CRISPR/Cas9 technology and pharmacological approaches to inactivate both proteins. We identify PTPN6 as a negative regulator of TNF-α-induced β-cell death, through JNK-dependent BCL-2 protein degradation. In contrast, PTPN1 acts as a positive regulator of IFN-γ-induced STAT1-dependent gene expression, which enhanced autoimmune destruction of β-cells. Importantly, PTPN1 inactivation by pharmacological modulation protects β-cells and primary mouse islets from cytokine-mediated cell death. Thus, our data point to a non-redundant effect of PTP regulation of cytokine signalling in β-cells in autoimmune diabetes.
Keywords: PTPN1; PTPN6; cytokines; inflammation; pancreatic β-cells; protein tyrosine phosphatases.
© 2017 Society for Endocrinology.