Abstract

Type 1 diabetes is characterized by the infiltration of activated leukocytes within the pancreatic islets, leading to β-cell dysfunction and destruction. The exact role played by interferon-γ, tumor necrosis factor (TNF)-α, and interleukin-1β 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, βTc-Tet. We previously reported that it was susceptible to apoptosis induced by TNF-α, in combination with interleukin-1β and interferon-γ. Here, we report that cytokine-induced apoptosis was correlated with the activation of caspase-8. We show that in βTc-Tet cells, overexpression of cFLIP, the cellular FLICE (FADD-like IL-1β-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-1β–mediated transcriptional activity of nuclear factor (NF)-κB, 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-α–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-γ alone could induce these β-cell dysfunctions. Together, our data demonstrate that overexpression of cFLIP protects mouse β-cells against TNF-α–induced caspase-8 activation and apoptosis and is correlated with enhanced NF-κB transcriptional activity, suggesting that cFLIP may have an impact on the outcome of death receptor–triggered responses by directing the intracellular signals from β-cell death to β-cell survival.