The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.
Cure of Chronic Viral Infection and Virus-Induced Type 1 Diabetes by Neutralizing Antibodies