title: RNase L contributes to experimentally induced type 1 diabetes onset in mice.
abstract: 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.
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Zipris
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Hongli
authors.initials: H
authors.lastname: Liu
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Malathi
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Jin
authors.affiliation: Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toledo, Toledo, Ohio 43606, USADepartment of Biological SciencesCase Western Reserve University School of Dental Medicine, Cleveland, Ohio 44106, USA Clinical Chemistry ProgramDepartment of Chemistry, Cleveland State University, SI 424, Cleveland, Ohio 44115, USACenter for Gene Regulation in Health and DiseasesCleveland State University, Cleveland, Ohio 44115, USADepartment of Cancer BiologyLerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USABarbara Davis Center of Childhood DiabetesUniversity of Colorado Health Science Center, Denver, Colorado 80045, USACentral Laboratorythe Eighth Hospital of Xi'an, 2 East Zhangba Road, Xi'an 710061, ChinaDepartment of Biological SciencesUniversity of Toled
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004722:Endoribonucleases / Q000172:deficiency* / Q000235:genetics; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C; D012330:RNA, Double-Stranded / Q000235:genetics; D051381:Rats; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012330:RNA, Double-Stranded; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D011070:Poly I-C
keywords: RNase L; immune cells; interferon; poly I:C; type 1 diabetes