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DOI: 10.2337/db05-1000
© 2006 by the American Diabetes Association
Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and ß-Cell Lines
1 Sarah W. Stedman Nutrition and Metabolism Center and the Department of Pharmacology and Cancer Biology, Duke University Medical Center Durham, Norh Carolina
2 Department of Medicine, Division of Endocrinology, Nutrition, and Metabolism, Duke University Medical Center, Durham, Norh Carolina
Address correspondence and reprint requests to Christopher B. Newgard, PhD, Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Duke Independence Park Facility, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. E-mail: newga002{at}mc.duke.edu
Abbreviations:
-IFN, -interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; siRNA, small interfering RNA
Type 1 diabetes results from islet ß-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1ß and -interferon are mediators of this ß-cell cytotoxicity, but the mechanism by which damage occurs is not well understood. In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat ß-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat ß-cell line selected for resistance to cytokine-induced cytotoxicity (833/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832/13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA–mediated suppression of the proapoptotic protein Bax enhances viability of 832/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin- and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both ß-cell lines and primary islets. We conclude that proinflammatory cytokines cause ß-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.
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