Activated T-cells and macrophages infiltrate pancreatic islets early in the pathogenesis of type 1 diabetes. Their secretion of different pro-inflammatory cytokines such as interleukin (IL)-1beta, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha affects beta-cell function. Here we report that a combination of these cytokines inhibits insulin release, stimulates inducible nitric oxide synthase (iNOS), and upregulates the surface expression of Fas in NIT-1 beta-cells and intact mouse islets. Using iNOS-deficient and Fas-deficient islets, respectively, we investigated the relative contribution of NO and Fas upregulation in cytokine-induced beta-cell damage. Interestingly, inhibition of insulin release did not occur in the absence of NO production. However, de novo expression of Fas-specific mRNA and Fas cell surface expression were detected and thus appear to be NO-independent. The lack of NO production partially protected islets from cytokine-induced apoptosis but had no effect on cell death induced by cell surface cross-linking of Fas with soluble Fas ligand (FasL). The absence of FasL on alpha-cells and the degree of apoptosis observed in Fas-deficient islets exclude the possibility of cytokine-induced fratricide. In conclusion, pro-inflammatory cytokines exert a cytotoxic effect on beta-cells via an NO-dependent pathway and, in parallel, render beta-cells susceptible to Fas:FasL-mediated, NO-independent cell death triggered by activated T-cells.
Abstract|
January 01 2000
Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage.
U Zumsteg;
U Zumsteg
Department of Research, University Children's Hospital, Basel, Switzerland. [email protected]
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S Frigerio;
S Frigerio
Department of Research, University Children's Hospital, Basel, Switzerland. [email protected]
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G A Holländer
G A Holländer
Department of Research, University Children's Hospital, Basel, Switzerland. [email protected]
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Citation
U Zumsteg, S Frigerio, G A Holländer; Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage.. Diabetes 1 January 2000; 49 (1): 39–47. https://doi.org/10.2337/diabetes.49.1.39
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