Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 2, Pages 929-941Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.162131
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Funding
- Fonds National de la Recherche Scientifique (FNRS-FRSM) Belgium
- Communaute Francaise de Belgique (Actions de Recherche Concertees)
- European Union (NAIMIT) [Health F22009-241447]
- Fonds National de la Recherche Scientifique, Belgium
- European Molecular Biology Organization
- Belgian government [IUAP P6/40]
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Cytokines produced by islet-infiltrating immune cells induce beta-cell apoptosis in type 1 diabetes. The IFN-gamma-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on beta-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in beta-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1 beta and IFN-gamma. Relevant microarray findings were further studied in INS-1E cells and primary rat beta-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated beta-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-gamma/STAT1/IRF-1 axis controls beta-cell function/differentiation, demise, and islet inflammation.
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