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Islet ß-Cell Apoptosis Triggered in Vivo by Interleukin-1ß Is Not Related to the Inducible Nitric Oxide Synthase Pathway: Evidence for Mitochondrial Function Impairment and Lipoperoxidation

Department of Surgical and Oncological Sciences (M.T., G.S.), School of Medicine, and Department of Medical Biotechnologies and Legal Medicine (F.D.G.), Section of Clinical Biochemistry, University of Palermo, 90127 Palermo, Italy; Dipartimento di Medicina Sperimentale (M.L.), Ambientale e Biotecnologie Mediche, Università Milano-Bicocca, 20125 Milano, Italy; and Department of Experimental Medicine (G.P.), Laboratory of Histology and Embryology, School of Medicine, 2nd University of Naples, 80138 Naples, Italy

Address all correspondence and requests for reprints to: Gianpaolo Papaccio, M.D., Ph.D., Department of Experimental Medicine, Laboratory of Histology, School of Medicine, 2nd University of Naples, 5 via L. Armanni, 80138 Naples, Italy. E-mail: gianpaolo.papaccio{at}unina2.it.

IL-1ß is recognized as an effector cytokine contributing to islet ß-cell destruction during diabetes. We have previously shown in vitro that IL-1ß induces nitric oxide (NO) and ß-cell damage. Here, we show that IL-1ß administration in vivo to Wistar rats transiently increases manganese superoxide dismutase activity, whereas inducible NO synthase is not detected, and the levels of nitrate+nitrate do not change. Moreover, a significant decrease of mitochondrial aconitase, leading to a rise of hydroperoxides, and islet ß-cell apoptosis, involving caspase-3 and -8, is observed. Analysis of adhesion molecules in ß-cells showed that intercellular adhesion molecule-1 is highly expressed 48 h after IL-1ß administration and that this is concomitant to the fall of manganese superoxide dismutase activity. Thus, IL-1ß exerts a proapoptotic effect in vivo through mitochondrial enzyme alteration, which is not related to the inducible NO synthase pathway, and dysregulates the immune system through the up-regulation of adhesion molecules.

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