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(American Journal of Pathology. 2001;159:273-283.)
© 2001 American Society for Investigative Pathology

Regular Articles

Mechanisms of ß-Cell Death in Response to Double-Stranded (ds) RNA and Interferon-{gamma}

dsRNA-Dependent Protein Kinase Apoptosis and Nitric Oxide-Dependent Necrosis

Anna L. Scarim*, Marc Arnush*, Libby A. Blair*, Josephine Concepcion*, Monique R. Heitmeier*, Donalyn Scheuner{dagger}, Randal J. Kaufman{ddagger}, Jan Ryerse§, R. Mark Buller and John A. Corbett*

From the Edward A. Doisy Department of Biochemistry and Molecular Biology,*
the Department of Pathology,§
the Department of Molecular Microbiology and Immunology,
Saint Louis University School of Medicine, St. Louis, Missouri; the Howard Hughes Medical Institute{dagger}
and the Department of Biological Chemistry,{ddagger}
University of Michigan, Ann Arbor, Michigan

Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate ß-cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs ß-cell function and induces ß-cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates ß-cell DNA damage and apoptosis without impairing islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-{gamma} stimulates DNA damage, apoptosis, and necrosis of islet cells, and this damage is associated with the inhibition of glucose-stimulated insulin secretion. Nitric oxide mediates the inhibitory and destructive actions of poly IC + IFN-{gamma} on insulin secretion and islet cell necrosis. Inhibitors of nitric oxide synthase, aminoguanidine, and NG-monomethyl-L-arginine, attenuate poly IC + IFN-{gamma}-induced DNA damage to levels observed in response to poly IC alone, prevent islet cell necrosis, and prevent the inhibitory actions on glucose-stimulated insulin secretion. NG-monomethyl-L-arginine fails to prevent poly IC- and poly IC + IFN-{gamma}-induced islet cell apoptosis. PKR, the dsRNA-dependent protein kinase that mediates the antiviral response in infected cells, is required for poly IC- and poly IC + IFN-{gamma}-induced islet cell apoptosis, but not nitric oxide-mediated islet cell necrosis. Alone, poly IC fails to stimulate DNA damage in islets isolated from PKR-deficient mice; however, nitric oxide-dependent DNA damage induced by the combination of poly IC + IFN-{gamma} is not attenuated by the genetic absence of PKR. These findings indicate that dsRNA stimulates PKR-dependent islet cell apoptosis, an event that is associated with normal islet secretory function. In contrast, poly IC + IFN-{gamma}-induced inhibition of glucose-stimulated insulin secretion and islet cell necrosis are events that are mediated by islet production of nitric oxide. These findings suggest that at least one IFN-{gamma}-induced antiviral response (islet cell necrosis) is mediated through a PKR-independent pathway.




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