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J Biol Chem, Vol. 274, Issue 18, 12531-12536, April 30, 1999

Double-stranded RNA Inhibits -Cell Function and Induces Islet Damage by Stimulating -Cell Production of Nitric Oxide

From the Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104

Viral infection has been implicated as a triggering event that may initiate -cell damage during the development of autoimmune diabetes. In this study, the effects of the viral replicative intermediate, double-stranded RNA (dsRNA) (in the form of synthetic polyinosinic-polycytidylic acid (poly IC)) on islet expression of inducible nitric oxide synthase (iNOS), production of nitric oxide, and islet function and viability were investigated. Treatment of rat islets with poly(IC) + interferon- (IFN-) stimulates the time- and concentration-dependent expression of iNOS and production of nitrite by rat islets. iNOS expression and nitrite production by rat islets in response to poly(IC) + IFN- correlate with an inhibition of insulin secretion and islet degeneration, effects that are prevented by the iNOS inhibitor aminoguanidine (AG). We have previously shown that poly(IC) + IFN- activates resident macrophages, stimulating iNOS expression, nitric oxide production and interleukin-1 (IL-1) release. In addition, in response to tumor necrosis factor- (TNF-) + lipopolysaccharide, activated resident macrophages mediate -cell damage via intraislet IL-1 release followed by IL-1-induced iNOS expression by -cells. The inhibitory and destructive effects of poly(IC) + IFN-, however, do not appear to require resident macrophages. Treatment of macrophage-depleted rat islets for 40 h with poly(IC) + IFN- results in the expression of iNOS, production of nitrite, and inhibition of insulin secretion. The destructive effects of dsRNA + IFN- on islets appear to be mediated by a direct interaction with -cells. Poly IC + IFN- stimulates iNOS expression and inhibits insulin secretion by primary -cells purified by fluorescence-activated cell sorting. In addition, AG prevents the inhibitory effects of poly(IC) + IFN- on glucose-stimulated insulin secretion by -cells. These results indicate that dsRNA + IFN- interacts directly with -cells stimulating iNOS expression and inhibiting insulin secretion in a nitric oxide-dependent manner. These findings provide biochemical evidence for a novel mechanism by which viral infection may directly mediate the initial destruction of -cells during the development of autoimmune diabetes.

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