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STAT1 Is a Master Regulator of Pancreatic β-Cell Apoptosis and Islet Inflammation

2010; Elsevier BV; Volume: 286; Issue: 2 Linguagem: Inglês

10.1074/jbc.m110.162131

1083-351X

Fabrice Moore, Najib Naamane, Máikel L. Colli, Thomas Bouckenooghe, Fernanda Ortis, Esteban N. Gurzov, Mariana Igoillo‐Esteve, Chantal Mathieu, Gianluca Bontempi, Thomas Thykjær, Torben F. Ørntoft, Décio L. Eizirik,

Diet, Metabolism, and Disease

Cytokines produced by islet-infiltrating immune cells induce β-cell apoptosis in type 1 diabetes. The IFN-γ-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on β-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 β-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1β and IFN-γ. Relevant microarray findings were further studied in INS-1E cells and primary rat β-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated β-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-γ/STAT1/IRF-1 axis controls β-cell function/differentiation, demise, and islet inflammation.