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.
Highlights
The inflammatory response to Double-stranded RNA (dsRNA) in NIT-1 cells is expected to be most representative of the inflammatory response to dsRNA that occurs in vivo in the Non-Obese Diabetic (NOD) mouse model, which triggers an autoimmune-mediated (Pattern A) form of type 1 diabetes mellitus (T1DM) [20,45,46]
Since we have previously shown that C10 is a potent inhibitor of dsRNA-induction of the same pro-inflammatory cytokines and chemokines involved in the development of T1DM (CXCL10, IFN, TNF, TLR3, and major histocompatibility (MHC) Class I) in other non-immune cell types [37,38,39,40], we hypothesized that C10 may be an important and potent inhibitor of dsRNA-induced production of these cytokines and chemokines in pancreatic beta cells
The results described indicate that C10 significantly protects beta cells from dsRNA-induced cytotoxicity and up-regulation of cytokines involved in beta cell destruction in beta cells in culture
Summary
Accumulating evidence supports a role for viruses in the pathogenesis of type 1 diabetes mellitus (T1DM) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. T1DM [24,30,31,32,33], and their therapeutic use in diseases, such as chronic active hepatitis, has triggered autoimmune diseases including T1DM [34] These type 1 interferons have been shown to accelerate the onset of diabetes in NOD mice, induce insulitis in diabetes resistant strains [35], and are present in the beta cells of recent-onset T1DM patients [31,36]. We demonstrated that C10 blocks dsRNA-induced IRF3 homodimer formation in pancreatic ductal epithelioid carcinoma cells [40], an important step in the TLR3 and RIG1 signaling pathways [23,41] This suggests that C10 may have biological activities that protect pancreatic beta cells from dsRNA-induced beta cell death and upregulation of many cytokines and chemokines involved in the pathogenesis of T1DM. These studies were designed to evaluate and describe potential beneficial biological effects C10 may have on preventing dsRNA activation of beta cell apoptosis and inflammatory pathways important in the development of T1DM as well as to evaluate efficacy of C10 to block viral acceleration of T1DM in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
