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Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells.
- Source :
-
Journal of molecular endocrinology [J Mol Endocrinol] 2017 Nov; Vol. 59 (4), pp. 325-337. Date of Electronic Publication: 2017 Aug 21. - Publication Year :
- 2017
-
Abstract
- 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.<br /> (© 2017 Society for Endocrinology.)
- Subjects :
- Animals
Cell Death genetics
Cell Death immunology
Gene Expression
Gene Knockout Techniques
Gene Targeting
Humans
JNK Mitogen-Activated Protein Kinases metabolism
Mice
Mice, Inbred NOD
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 1 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Protein Tyrosine Phosphatases genetics
T-Lymphocytes immunology
T-Lymphocytes metabolism
Tumor Necrosis Factor-alpha metabolism
Cytokines metabolism
Inflammation Mediators metabolism
Insulin-Secreting Cells metabolism
Protein Tyrosine Phosphatases metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1479-6813
- Volume :
- 59
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of molecular endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 28827413
- Full Text :
- https://doi.org/10.1530/JME-17-0089