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Improvement of the Mitochondrial Antioxidant Defense Status Prevents Cytokine-Induced Nuclear Factor-B Activation in Insulin-Producing Cells

¹ Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
² Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
³ Laboratory of Experimental Medicine, Free University Brussels, Brussels, Belgium

Proinflammatory cytokines (interleukin-1ß [IL-1ß], tumor necrosis factor- [TNF-], and -interferon [IFN-]) initiate a variety of signal cascades in pancreatic ß-cells that affect the expression level of genes involved in both the destruction and the protection of the ß-cell. The generation of nitric oxide (NO) via the inducible NO synthase (iNOS) and oxygen free radicals play a key role in cytokine-mediated ß-cell destruction. Within these signal cascades, the activation of the transcription factor nuclear factor-B (NF-B) is crucial, and many cytokine-sensitive genes contain binding sites for this transcription factor in their promoter regions. The aim of this study was to characterize the cytokine-mediated activation of NF-B and the subsequent expression of iNOS protein in insulin-producing RINm5F cells with an improved antioxidant defense status by overexpression of the cytoprotective enzymes catalase (Cat), glutathione peroxidase (Gpx), and the cytoplasmic Cu/Zn superoxide dismutase (Cu/ZnSOD). RINm5F cells with diverse mitochondrial antioxidative defense status were generated by stable overexpression of MnSOD constructs in sense (MnSOD sense) and antisense orientation (MnSOD antisense). Cytokine-induced (IL-1ß or cytokine mix consisting of IL-1ß + TNF- + IFN-) activation of NF-B in RINm5F cells was reduced by >80% through overexpression of MnSOD. The activity of the iNOS promoter remained at basal levels in cytokine-stimulated MnSOD sense cells. In contrast, the suppression of MnSOD gene expression in cytokine-stimulated MnSOD antisense cells resulted in a threefold higher activation of NF-B and a twofold higher activation of the iNOS promoter as compared with control cells. The iNOS protein expression was significantly reduced after a 6- and 8-h cytokine incubation of MnSOD sense cells. The low activity level of MnSOD in RINm5F MnSOD antisense cells increased the iNOS protein expression in particular during the early phase of cytokine-mediated toxicity. Cat, Gpx, and the cytoplasmic Cu/ZnSOD did not affect the activation of NF-B and the iNOS promoter. In conclusion, the overexpression of MnSOD, which inactivates specifically mitochondrially derived oxygen free radicals, significantly reduced the activation of NF-B in insulin-producing cells. As a consequence of this protective effect in the early cytokine signaling pathways, the induction of iNOS, an important event in the ß-cell destruction process, was also significantly reduced. The results provide evidence that mitochondrially derived reactive oxygen species (ROS) play a critical role in the activation of the cytokine-sensitive transcription factor NF-B. Overexpression of MnSOD may thus be beneficial for ß-cell survival through suppression of oxygen free radical formation, prevention of NF-B activation, and iNOS expression.

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