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© 2001 by the American Diabetes Association, Inc.
Cytokine Induction of Fas Gene Expression in Insulin-Producing Cells Requires the Transcription Factors NF-
B and C/EBP
Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
Fas-mediated cell death may play a role in the autoimmune destruction of pancreatic ß-cells in type 1 diabetes. ß-Cells do not express Fas under physiological conditions, but Fas mRNA and protein are induced in cytokine-exposed mouse and human islets, rendering the ß-cells susceptible to Fas ligand–induced apoptosis. The aim of the present study was to investigate the molecular regulation of Fas by cytokines in rat ß-cells and in insulin-producing RINm5F cells. Fas mRNA expression was increased 15-fold in fluorescence-activated cell sorting–purified rat ß-cells exposed to interleukin (IL)-1ß, whereas 
-interferon had no effect. Transfection experiments of rat Fas promoter-luciferase reporter constructs into purified rat ß-cells and RINm5F insulinoma cells identified an IL-1ß–responsive region between nucleotides -223 and -54. Inactivation of two adjacent NF-
B and C/EBP sites in this region abolished IL-1ß–induced Fas promoter activity in RINm5F cells. Binding of NF-B and C/EBP factors to their respective sites was confirmed by gel shift assays. In cotransfection experiments, NF-B p65 transactivated the Fas promoter. NF-B p50 and C/EBPß overexpression had no effect by themselves on the Fas promoter activity, but when cotransfected with p65, each factor inhibited transactivation by p65. These results suggest a critical role for NF-B and C/EBP factors in cytokine-regulation of Fas expression in insulin-producing cells.
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