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

  1. Fabrice Moore1,
  2. Maikel L. Colli1,
  3. Miriam Cnop1,2,
  4. Mariana Igoillo Esteve1,
  5. Alessandra K. Cardozo1,
  6. Daniel A. Cunha1,
  7. Marco Bugliani3,
  8. Piero Marchetti3 and
  9. Décio L. Eizirik1
  1. 1Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium;
  2. 2Division of Endocrinolbogy, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium;
  3. 3Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
  1. 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.S.C. Section 1734 solely to indicate this fact.

    • Received October 31, 2008.
    • Accepted March 16, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 58 no. 6 1283-1291
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