Article: article from journal or magazin.
cFLIP protein prevents tumor necrosis factor-alpha-mediated induction of caspase-8-dependent apoptosis in insulin-secreting betaTc-Tet cells.
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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-1beta 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, betaTc-Tet. We previously reported that it was susceptible to apoptosis induced by TNF-alpha, in combination with interleukin-1beta and interferon-gamma. Here, we report that cytokine-induced apoptosis was correlated with the activation of caspase-8. We show that in betaTc-Tet cells, overexpression of cFLIP, the cellular FLICE (FADD-like IL-1beta-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-1beta-mediated transcriptional activity of nuclear factor (NF)-kappaB, 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-kappaB transcriptional activity, suggesting that cFLIP may have an impact on the outcome of death receptor-triggered responses by directing the intracellular signals from beta-cell death to beta-cell survival.
Animals, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins/genetics, Carrier Proteins/physiology, Caspase 8, Caspase 9, Caspases/metabolism, Cell Line, Enzyme Activation/drug effects, Gene Expression, Glucose/pharmacology, Humans, Insulin/secretion, Interferon-gamma/pharmacology, Interleukin-1/pharmacology, Intracellular Signaling Peptides and Proteins, Islets of Langerhans/cytology, Islets of Langerhans/secretion, Mice, Mice, Transgenic, NF-kappa B/metabolism, Nitric Oxide/metabolism, Nitric Oxide Synthase/genetics, Nitric Oxide Synthase Type II, Recombinant Proteins, Transcription, Genetic, Transfection, Tumor Necrosis Factor-alpha/pharmacology
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