Notch signaling: a mediator of beta-cell de-differentiation in diabetes?
Cytokines are mediators of pancreatic beta-cell dysfunction and death in type 1 diabetes mellitus. Microarray analyses of insulin-producing cells exposed to interleukin-1beta+interferon-gamma showed decreased expression of genes related to beta-cell-differentiated functions and increased expression of members of the Notch signaling pathway. Re-expression of this developmental pathway may contribute for loss-of-function of beta-cells exposed to an autoimmune attack. In this study, we show that rat primary beta-cells exposed to cytokines up-regulate several Notch receptors and ligands, and the target gene Hes1. Transfection of insulin-producing INS-1E cells and primary rat beta-cells with a constitutively active form of the Notch receptor down-regulated Pdx1 and insulin expression in INS-1E cells but not in primary beta-cells. Thus, activation of the Notch pathway inhibits differentiated functions in dividing but not in terminally differentiated beta-cells.
Darville
Martine I
MI
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Belgium. mdarvill@ulb.ac.be
Eizirik
Décio L
DL
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D007328:Insulin; D051880:Receptors, Notch