cFLIP protein prevents tumor necrosis factor-[alpha]-mediated induction of caspase-8--dependent apoptosis in insulin-secreting [beta]Tc-Tet cells

Type 1 diabetes is characterized by the infiltration of activated leukocytes within the pancreatic islets, leading to [beta]-cell dysfunction and destruction. The exact role played by interferon-[gamma] tumor necrosis factor (TNF)-[alpha] and interleukin-1[beta] 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, [beta]Tc-Tet. We previously reported that it was susceptible to apoptosis induced by TNF-[alpha], in combination with interleukin-1[beta] and interferon-[gamma]. Here, we report that cytokine-induced apoptosis was correlated with the activation of caspase-8. We show that in [beta]Tc-Tet cells, overexpression of cFLIP, the cellular FLICE (FADD-like IL-1[beta]-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-1[beta]-mediated transcriptional activity of nuclear factor (NF)-[kappa]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-[alpha]-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-[gamma] alone could induce these [beta]-cell dysfunctions. Together, our data demonstrate that overexpression of cFLIP protects mouse [beta]-cells against TNF-[alpha]-induced caspase-8 activation and apoptosis and is correlated with enhanced NF-[kappa]B transcriptional activity, suggesting that cFLIP may have an impart on the outcome of death receptor-triggered responses by directing the intracellular signals from [beta]-cell death to [beta]-cell survival. Diabetes 51:1805-1814, 2002