期刊
DIABETES
卷 58, 期 6, 页码 1283-1291出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-1510
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资金
- Fonds National de la Recherche Scientifique (FNRS-FRSM) Belgium
- Communaute Francaise de Belgique-Actions de Recherche Concertees (ARC)
- European Union (STREP Savebeta) [036903]
- Belgium State [IUAP P6/40]
- FNRS, Belgium
- CAPES (Brazilian Coordination for the Improvement of Higher Education Personnel)
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 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. 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 beta-cells, allowing the assessment of cell death after cytokine treatment. RESULTS-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)-1 beta + 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. CONCLUSIONS-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. Diabetes 58:1283-1291, 2009
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