Abstract

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