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cFLIP Protein Prevents Tumor Necrosis Factor-–Mediated Induction of Caspase-8–Dependent Apoptosis in Insulin-Secreting ßTc-Tet Cells

Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Type 1 diabetes is characterized by the infiltration of activated leukocytes within the pancreatic islets, leading to ß-cell dysfunction and destruction. The exact role played by interferon-, tumor necrosis factor (TNF)-, and interleukin-1ß in this pathogenic process is still only partially understood. To study cytokine action at the cellular level, we are working with the highly differentiated insulin-secreting cell line, ßTc-Tet. We previously reported that it was susceptible to apoptosis induced by TNF-, in combination with interleukin-1ß and interferon-. Here, we report that cytokine-induced apoptosis was correlated with the activation of caspase-8. We show that in ßTc-Tet cells, overexpression of cFLIP, the cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein, completely abolished cytokine-dependent activation of caspase-8 and protected the cells against apoptosis. Furthermore, cFLIP overexpression increased the basal and interleukin-1ß–mediated transcriptional activity of nuclear factor (NF)-B, whereas it did not change cytokine-induced inducible nitric oxide synthase gene transcription and nitric oxide secretion. The presence of cFLIP prevented the weak TNF-–induced reduction in cellular insulin content and secretion; however, it did not prevent the decrease in glucose-stimulated insulin secretion induced by the combined cytokines, in agreement with our previous data demonstrating that interferon- alone could induce these ß-cell dysfunctions. Together, our data demonstrate that overexpression of cFLIP protects mouse ß-cells against TNF-–induced caspase-8 activation and apoptosis and is correlated with enhanced NF-B transcriptional activity, suggesting that cFLIP may have an impact on the outcome of death receptor–triggered responses by directing the intracellular signals from ß-cell death to ß-cell survival.

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