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Cytokine-Induced Proapoptotic Gene Expression in Insulin-Producing Cells Is Related to Rapid, Sustained, and Nonoscillatory Nuclear Factor-B Activation

Laboratory of Experimental Medicine (F.O., A.K.C., D.C., D.L.E.), Université Libre de Bruxelles, 1070 Brussels, Belgium; Laboratory for ß-Cell Biology (J.S., T.M.-P.), Steno Diabetes Center, DK-2820 Gentofte, Denmark; and Department of Molecular Medicine (T.M.-P.), Karolinska Institute, SE-17177 Stockholm, Sweden

Address all correspondence and requests for reprints to: Professor Décio L. Eizirik, Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808-CP-618, 1070 Brussels, Belgium. E-mail: deizirik{at}ulb.ac.be.

Cytokines, such as IL-1ß and TNF-, contribute to pancreatic ß-cell death in type 1 diabetes mellitus. The transcription factor nuclear factor-B (NF-B) mediates cytokine-induced ß-cell apoptosis. Paradoxically, NF-B has mostly antiapoptotic effects in other cell types. The cellular actions of NF-B depend on the cell type, the nature and duration of the stimulus, the periodicity, and the degree of activity of the particular dimers involved. To clarify the reasons behind the proapoptotic effects of NF-B in pancreatic ß-cells, we compared the pattern of cytokine-induced NF-B activation between rat insulin-producing cells (INS-1E cells) and fibroblasts (208F cells). NF-B activation was induced in INS-1E cells and in 208F cells after exposure to cytokines, but apoptosis was induced only in INS-1E cells, with a more pronounced proapoptotic effect of IL-1ß than of TNF-. NF-B activation in IL-1ß-exposed INS-1E cells was earlier and more marked as compared with TNF--exposed INS-1E cells or IL-1ß-exposed 208F cells. Both cytokines induced a prolonged (up to 48 h) and stable NF-B activation in INS-1E cells, whereas IL-1ß induced an oscillatory NF-B activation in 208F cells. p65/p65 and p65/p50 were the predominant NF-B dimers in IL-1ß-exposed INS-1E cells and 208F cells, respectively. IL-1ß induced a differential usage of cis-elements in the inducible nitric oxide synthase promoter region in the two cell-lines and an increase in ERK1/2 activity in INS-1E cells but not in 208F cells. Cytokine-induced expression of IB isoforms and other NF-B target genes (Fas, MCP-1, and inducible nitric oxide synthase) was severalfold higher in INS-1E cells than in 208F cells. These results suggest that cytokine-induced NF-B activation in insulin-producing cells is more rapid, marked, and sustained than in fibroblasts, which correlates with a more pronounced activation of downstream genes and a proapoptotic outcome.

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