Journal Article

MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA

Maikel L. Colli, Fabrice Moore, Esteban N. Gurzov, Fernanda Ortis and Decio L. Eizirik

in Human Molecular Genetics

Volume 19, issue 1, pages 135-146
Published in print January 2010 | ISSN: 0964-6906
Published online October 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp474
MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA

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β-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a ‘dialog’ between β-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects β-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic β-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat β-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic–polycitidilic acid—PIC). Real-time RT–PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary β-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify β-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate β-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic β-cell level.

Journal Article.  6896 words.  Illustrated.

Subjects: Genetics and Genomics

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