Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage.
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.
Zumsteg
U
U
Department of Research, University Children's Hospital, Basel, Switzerland. zumstegu@ubaclu.unibas.ch
Frigerio
S
S
Holländer
G A
GA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D053222:Fas Ligand Protein; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007328:Insulin; D008562:Membrane Glycoproteins; D019014:fas Receptor; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse