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Free Radicals and the Pathogenesis of Type 1 Diabetes

ß-Cell Cytokine-Mediated Free Radical Generation Via Cyclooxygenase-2

From the Free Radical Biology & Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

Free radical formation evoked by proinflammatory cytokines has been suggested to be involved in the destruction of ß-cells in the course of type 1 diabetes development. However, there is no direct evidence to support this hypothesis. In this study, we used electron paramagnetic resonance spectroscopy in conjunction with spin-trapping methodology to directly determine whether cytokines give rise to free radical formation in the islets. Our results demonstrate that direct, in vivo administration of tumor necrosis factor- (1,000 units), interleukin-1ß (1,000 units), and interferon- (2,000 units) into the rat pancreas through a bile duct cannula leads to the formation of lipid-derived free radicals in this tissue. These free radicals most likely are generated by the ß-cells because previous depletion of these cells by streptozotocin abolished the cytokine-induced free radical formation. Furthermore, macrophage depletion was found to decrease the production of free radicals. Inhibition of the enzyme inducible cyclooxygenase (COX-2) and the transcription factor nuclear factor-B (NF-B) significantly diminished the free radicals’ signal intensity, implicating these factors in the formation of free radicals. We have also demonstrated that cytokine treatment leads to the activation of NF-B in the pancreatic islets of the rats.

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