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Cytokines Induce Both Necrosis and Apoptosis via a Common Bcl-2-Inhibitable Pathway in Rat Insulin-Producing Cells¹

Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. J. Saldeen, Department of Medical Cell Biology, Biomedicum, Uppsala University, P.O. Box 571, S-751 23 Uppsala, Sweden. E-mail: johan.saldeen{at}medcellbiol.uu.se

The presence of activated macrophages within pancreatic islets in insulin-dependent diabetes mellitus suggests an involvement of ß-cell death by necrosis. The aim of this study was to investigate the frequencies and mechanisms of cytokine-induced ß-cell apoptosis and necrosis and the possible protection mediated by the antiapoptotic gene bcl-2. A combination of interleukin-1ß, interferon-, and tumor necrosis factor- increased both necrosis (17% of cells) and apoptosis (5% of cells) in isolated whole rat islets, as determined by vital staining and fluorescence microscopy. Hyperexpression of Bcl-2, achieved by stable transfection using a multicopy viral vector containing a bcl-2 complementary DNA in rat insulin-producing RINm5F cells, counteracted both apoptosis and necrosis. Cytokine-induced cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (which, in other cell types, may occur downstream or independently of a Bcl-2-preventable mitochondrial permeability transition) was observed in control- but neither in bcl-2-transfected cells nor in the presence of the iNOS inhibitor N^G-methyl-L-arginine. Tumor necrosis factor- alone did not clearly induce cell death or poly(ADP-ribose) polymerase-cleavage. These findings suggest that cytokines induce both necrosis and apoptosis in insulin-producing cells via a common Bcl-2-preventable nitric oxide-dependent pathway, which may involve mitochondrial permeability transition. The necrosis:apoptosis ratio might be increased by a relative lack of caspase activity.

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