Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-γ: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent …

AL Scarim, M Arnush, LA Blair, J Concepcion… - The American journal of …, 2001 - Elsevier
AL Scarim, M Arnush, LA Blair, J Concepcion, MR Heitmeier, D Scheuner, RJ Kaufman
The American journal of pathology, 2001Elsevier
Viral infection is one environmental factor that has been implicated as a precipitating event
that may initiate β-cell damage during the development of diabetes. This study examines the
mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs β-
cell function and induces β-cell death. The synthetic dsRNA molecule polyinosinic-
polycytidylic acid (poly IC) stimulates β-cell DNA damage and apoptosis without impairing
islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-γ …
Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate β-cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs β-cell function and induces β-cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates β-cell DNA damage and apoptosis without impairing islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-γ 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-γ on insulin secretion and islet cell necrosis. Inhibitors of nitric oxide synthase, aminoguanidine, and NG-monomethyl-l-arginine, attenuate poly IC + IFN-γ-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-γ-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-γ-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-γ 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-γ-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-γ-induced antiviral response (islet cell necrosis) is mediated through a PKR-independent pathway.
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