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- Title
PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis.
- Authors
Moore F; Colli ML; Cnop M; Esteve MI; Cardozo AK; Cunha DA; Bugliani M; Marchetti P; Eizirik DL; Moore, Fabrice; Colli, Maikel L; Cnop, Miriam; Esteve, Mariana Igoillo; Cardozo, Alessandra K; Cunha, Daniel A; Bugliani, Marco; Marchetti, Piero; Eizirik, Décio L
- Abstract
<bold>Objective: </bold>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 beta-cell demise and assessed PTPN2 expression in human islets and rat primary and clonal beta-cells, besides evaluating its role in cytokine-induced signaling and beta-cell apoptosis.<bold>Research Design and Methods: </bold>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 beta-cells, allowing the assessment of cell death after cytokine treatment.<bold>Results: </bold>PTPN2 mRNA and protein are expressed in human islets and rat beta-cells and upregulated by cytokines. Transfection with PTPN2 siRNAs inhibited basal- and cytokine-induced PTPN2 expression in rat beta-cells and dispersed human islets cells. Decreased PTPN2 expression exacerbated interleukin (IL)-1beta + interferon (IFN)-gamma-induced beta-cell apoptosis and turned IFN-gamma alone into a proapoptotic signal. Inhibition of PTPN2 amplified IFN-gamma-induced STAT1 phosphorylation, whereas double knockdown of both PTPN2 and STAT1 protected beta-cells against cytokine-induced apoptosis, suggesting that STAT1 hyperactivation is responsible for the aggravation of cytokine-induced beta-cell death in PTPN2-deficient cells.<bold>Conclusions: </bold>We identified a functional role for the type 1 diabetes candidate gene PTPN2 in modulating IFN-gamma signal transduction at the beta-cell level. PTPN2 regulates cytokine-induced apoptosis and may thereby contribute to the pathogenesis of type 1 diabetes.
- Publication
Diabetes, 2009, Vol 58, Issue 6, p1283
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db08-1510