STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.
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.
Moore
Fabrice
F
Laboratory of Experimental Medicine, Université Libre de Bruxelles, B-1070 Brussels, Belgium.
Naamane
Najib
N
Colli
Maikel L
ML
Bouckenooghe
Thomas
T
Ortis
Fernanda
F
Gurzov
Esteban N
EN
Igoillo-Esteve
Mariana
M
Mathieu
Chantal
C
Bontempi
Gianluca
G
Thykjaer
Thomas
T
Ørntoft
Torben F
TF
Eizirik
Decio L
DL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000502:physiology; D055785:Gene Knockdown Techniques; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology*; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology; D010195:Pancreatitis / Q000276:immunology* / Q000473:pathology*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; C484585:Hrk protein, rat; D050856:Interferon Regulatory Factor-1; D053583:Interleukin-1beta; D009479:Neuropeptides; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D007371:Interferon-gamma