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MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2010 Jan 01; Vol. 19 (1), pp. 135-46. - Publication Year :
- 2010
-
Abstract
- beta-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a 'dialog' between beta-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 beta-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 beta-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-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 beta-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 beta-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 beta-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 beta-cell level.
- Subjects :
- Animals
Apoptosis drug effects
Chemokines metabolism
Enzyme Activation drug effects
Insulin-Secreting Cells enzymology
Interferon-beta genetics
JNK Mitogen-Activated Protein Kinases metabolism
Male
NF-kappa B metabolism
Poly I-C pharmacology
Promoter Regions, Genetic genetics
RNA, Small Interfering metabolism
Rats
Rats, Wistar
DEAD-box RNA Helicases metabolism
Diabetes Mellitus, Type 1 enzymology
Diabetes Mellitus, Type 1 genetics
Insulin-Secreting Cells pathology
Protein Tyrosine Phosphatase, Non-Receptor Type 2 metabolism
RNA, Double-Stranded pharmacology
Viruses metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 19
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 19825843
- Full Text :
- https://doi.org/10.1093/hmg/ddp474