TY - JOUR
T1 - RNase L contributes to experimentally induced type 1 diabetes onset in mice
AU - Zeng, Chun
AU - Yi, Xin
AU - Zipris, Danny
AU - Liu, Hongli
AU - Zhang, Lin
AU - Zheng, Qiaoyun
AU - Malathi, Krishnamurthy
AU - Jin, Ge
AU - Zhou, Aimin
N1 - Publisher Copyright:
© 2014 Society for Endocrinology.
PY - 2014
Y1 - 2014
N2 - 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), amimicof viral infection, is associatedwiththeonset of type1diabetes.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 diabetesonset throughregulatingimmune 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.
AB - 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), amimicof viral infection, is associatedwiththeonset of type1diabetes.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 diabetesonset throughregulatingimmune 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.
KW - Immune cells
KW - Interferon
KW - Poly I:C
KW - RNase L
KW - Type 1 diabetes
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U2 - 10.1530/JOE-14-0509
DO - 10.1530/JOE-14-0509
M3 - Article
C2 - 25287058
AN - SCOPUS:84911977350
SN - 0022-0795
VL - 223
SP - 277
EP - 287
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 3
ER -