title: Phenylmethimazole suppresses dsRNA-induced cytotoxicity and inflammatory cytokines in murine pancreatic beta cells and blocks viral acceleration of type 1 diabetes in NOD mice.
abstract: Accumulating evidence supports a role for viruses in the pathogenesis of type 1 diabetes mellitus (T1DM). Activation of dsRNA-sensing pathways by viral dsRNA induces the production of inflammatory cytokines and chemokines that trigger beta cell apoptosis, insulitis, and autoimmune-mediated beta cell destruction. This study was designed to evaluate and describe potential protective effects of phenylmethimazole (C10), a small molecule which blocks dsRNA-mediated signaling, on preventing dsRNA activation of beta cell apoptosis and the inflammatory pathways important in the pathogenesis of T1DM. We first investigated the biological effects of C10, on dsRNA-treated pancreatic beta cells in culture. Cell viability assays, quantitative real-time PCR, and ELISAs were utilized to evaluate the effects of C10 on dsRNA-induced beta cell cytotoxicity and cytokine/chemokine production in murine pancreatic beta cells in culture. We found that C10 significantly impairs dsRNA-induced beta cell cytotoxicity and up-regulation of cytokines and chemokines involved in the pathogenesis of T1DM, which prompted us to evaluate C10 effects on viral acceleration of T1DM in NOD mice. C10 significantly inhibited viral acceleration of T1DM in NOD mice. These findings demonstrate that C10 (1) possesses novel beta cell protective activity which may have potential clinical relevance in T1DM and (2) may be a useful tool in achieving a better understanding of the role that dsRNA-mediated responses play in the pathogenesis of T1DM.
authors.affiliation: Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701, USA. mccallk@ohio.edu
authors.forename: Kelly D
authors.initials: KD
authors.lastname: McCall
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schmerr
authors.forename: Jean R
authors.initials: JR
authors.lastname: Thuma
authors.forename: Calvin B L
authors.initials: CB
authors.lastname: James
authors.forename: Maria C
authors.initials: MC
authors.lastname: Courreges
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Ramiro
authors.initials: R
authors.lastname: Malgor
authors.forename: Frank L
authors.initials: FL
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control* / Q000821:virology; D004770:Enterovirus / Q000378:metabolism / Q000472:pathogenicity*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008713:Methimazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D012330:RNA, Double-Stranded / Q000009:adverse effects*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013871:Thiones / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D016207:Cytokines; D012330:RNA, Double-Stranded; C519703:TLR3 protein, mouse; D013871:Thiones; D051196:Toll-Like Receptor 3; C489637:phenyl methimazole; D008713:Methimazole
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