Dominance of cytokine- over FasL-induced impairment of the mitochondrial transmembrane potential (ΔΨm) in the pancreatic β-cell line NIT-1

Mitochondria of pancreatic β-cells are potential targets of intrinsic and extrinsic apoptotic pathways in the autoimmune pathogenesis of type 1 diabetes. We aimed to investigate whether cytokine- and FasLigand (FasL)-induced apoptosis is associated with impaired mitochondrial transmembrane potential...

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Veröffentlicht in:Diabetes & vascular disease research 2008-09, Vol.5 (3), p.198-204
Hauptverfasser: Augstein, Petra, Heinke, Peter, Salzsieder, Eckhard, Grimm, Rita, Giebel, Jürgen, Salzsieder, Christel, Harrison, Leonard C
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Sprache:eng
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Zusammenfassung:Mitochondria of pancreatic β-cells are potential targets of intrinsic and extrinsic apoptotic pathways in the autoimmune pathogenesis of type 1 diabetes. We aimed to investigate whether cytokine- and FasLigand (FasL)-induced apoptosis is associated with impaired mitochondrial transmembrane potential (ΔΨm) in the pancreatic β-cell line NIT-1. NIT-1 cells were exposed to the interleukin-1 β/interferon-γ (IL-1 β/IFN-γ) cytokine combination to induce apoptosis in vitro. Low concentrations of cytokines resulted in ΔΨm impairment, and increasing concentrations had only a minor additional effect. Treatment with the inducible nitric oxide synthase (iNOS) inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) prevented cytokine-mediated ΔΨm impairment, implying that cytokines affect ΔΨm via nitric oxide. The broad-spectrum caspase inhibitor Z-VAD(Ome)-FMK (ZVAD) revealed dichotomic actions. In the presence of ZVAD, cytokine-induced nitrite generation was increased but cell death and ΔΨm impairment were reduced. ΔΨm impairment was also reduced by inhibitors of caspases 1, 6 and 8. Induction of Fas by IL-1 β/IFN-γ coupled with activation by Super-FasL augmented cytokine-induced cell death. We observed a clear dominance of cytokine- over FasL-induced effects on ΔΨm. Our findings show that IL-1 β/IFN-γ cytokines have a strong effect to impair ΔΨm and prime β-cells for apoptosis via the intrinsic pathway mediated by iNOS and caspases. Furthermore, at least in NIT-1 cells, the extrinsic FasL/Fas pathway has only a minor additive effect on cytokine-induced ΔΨm impairment.
ISSN:1479-1641
1752-8984
DOI:10.3132/dvdr.2008.032