PTPN2, a Candidate Gene for Type 1 Diabetes, Modulates Interferon-γ–Induced Pancreatic β-Cell Apoptosis

PTPN2, a Candidate Gene for Type 1 Diabetes, Modulates Interferon-γ–Induced Pancreatic β-Cell Apoptosis Fabrice Moore 1 , Maikel L. Colli 1 , Miriam Cnop 1 , 2 , Mariana Igoillo Esteve 1 , Alessandra K. Cardozo 1 , Daniel A. Cunha 1 , Marco Bugliani 3 , Piero Marchetti 3 and Décio L. Eizirik 1 1 Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium; 2 Division of Endocrinolbogy, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium; 3 Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy. Corresponding author: Fabrice Moore, fmoore{at}ulb.ac.be . Abstract OBJECTIVE The pathogenesis of type 1 diabetes has a strong genetic component. Genome-wide association scans recently identified novel susceptibility genes including the phosphatases PTPN22 and PTPN2. We hypothesized that PTPN2 plays a direct role in β-cell demise and assessed PTPN2 expression in human islets and rat primary and clonal β-cells, besides evaluating its role in cytokine-induced signaling and β-cell apoptosis. RESEARCH DESIGN AND METHODS PTPN2 mRNA and protein expression was evaluated by real-time PCR and Western blot. Small interfering (si)RNAs were used to inhibit the expression of PTPN2 and downstream STAT1 in β-cells, allowing the assessment of cell death after cytokine treatment. RESULTS PTPN2 mRNA and protein are expressed in human islets and rat β-cells and upregulated by cytokines. Transfection with PTPN2 siRNAs inhibited basal- and cytokine-induced PTPN2 expression in rat β-cells and dispersed human islets cells. Decreased PTPN2 expression exacerbated interleukin (IL)-1β + interferon (IFN)-γ–induced β-cell apoptosis and turned IFN-γ alone into a proapoptotic signal. Inhibition of PTPN2 amplified IFN-γ–induced STAT1 phosphorylation, whereas double knockdown of both PTPN2 and STAT1 protected β-cells against cytokine-induced apoptosis, suggesting that STAT1 hyperactivation is responsible for the aggravation of cytokine-induced β-cell death in PTPN2-deficient cells. CONCLUSIONS We identified a functional role for the type 1 diabetes candidate gene PTPN2 in modulating IFN-γ signal transduction at the β-cell level. PTPN2 regulates cytokine-induced apoptosis and may thereby contribute to the pathogenesis of type 1 diabetes. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U