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

• Published in: The American journal of pathology Vol. 159; no. 1; pp. 273 - 283
• Main Authors: SCARIM, Anna L, ARNUSH, Marc, BLAIR, Libby A, CONCEPCION, Josephine, HEITMEIER, Monique R, SCHEUNER, Donalyn, KAUFMAN, T. Randal J, RYERSE, Jan, BULLER, R. Mark, CORBETT, John A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Investigative Pathology 01.07.2001
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Cell Death - physiology; Cells, Cultured; Diabetes. Impaired glucose tolerance; DNA Damage - physiology; Drug Synergism; eIF-2 Kinase - physiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - pharmacology; Insulin - metabolism; Insulin Secretion; Interferon-gamma - pharmacology; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Islets of Langerhans - ultrastructure; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout - genetics; Microscopy, Electron; Necrosis; Nitric Oxide - physiology; Poly I-C - pharmacology; Protein Kinases - physiology; Rats; Rats, Sprague-Dawley; Regular; RNA, Double-Stranded - pharmacology; Endocrinopathy; Immunohistochemistry; Double stranded RNA; Rat; Enzyme; Pathogenesis; Transferases; Diabetes mellitus; Cytokine; Rodentia; Langerhans islet; Electron microscopy; Infection; Pathology; Vertebrata; Experimental disease; Mammalia; Cell death; Protein kinase; Animal; Nitric oxide; Viral disease; Apoptosis; Gamma interferon
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)61693-8

Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate beta-cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs beta-cell function and induces beta-cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates beta-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 N(G)-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. N(G)-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.