PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis

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 up-regulated 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 IL-1β + IFN-γ-induced β-cell apoptosis, and turned IFN-γ alone into a pro-apoptotic signal. Inhibition of PTPN2 amplified IFN-γ-induced STAT1 phosphorylation while 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.