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Variations in IB1/JIP1 Expression Regulate Susceptibility of ß-Cells to Cytokine-Induced Apoptosis Irrespective of C-Jun NH₂-Terminal Kinase Signaling

¹ Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium
² Department of Internal Medicine B, University Hospital, Lausanne, Switzerland

We previously reported that interleukin-1ß (IL-1ß) alone does not cause apoptosis of ß-cells, whereas when combined with -interferon (IFN-) and tumor necrosis factor- (TNF-), it exerts a distinct apoptotic effect. Studies in ß-cell lines indicated that IL-1ß reduced expression of islet brain (IB)-1/JNK interacting protein (JIP)-1, a JNK scaffold protein with antiapoptotic action. We examined whether variations in IB1/JIP-1 expression in purified primary ß-cells affect their susceptibility to cytokine-induced apoptosis. Exposure to IL-1ß for 24 h decreased cellular IB1/JIP-1 content by 66 ± 17%; this IL-1ß effect was maintained in the presence of TNF- + IFN-, which did not influence IB1/JIP-1 levels by themselves. Addition of IL-1ß to TNF- + IFN- increased apoptosis from 20 ± 2% to 59 ± 5%. A similar increase in TNF- + IFN--induced apoptosis was produced by adenoviral expression of antisense IB1/JIP-1 and was not further enhanced by addition of IL-1ß, indicating that IL-1ß-mediated suppression of IB1/JIP-1 in ß-cells increases their susceptibility to cytokine-induced apoptosis. However, adenovirally mediated overexpression of IB1/JIP-1 also potentiated TNF- + IFN--induced apoptosis, suggesting that the antiapoptotic effect of IB1/JIP-1 depends on well-defined cellular levels. We conclude that the IB1/JIP-1 level in ß-cells can control their susceptibility to apoptosis independent of JNK signaling.

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