MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p Regulate the Expression of Proapoptotic BH3-Only Proteins DP5 and PUMA in Human Pancreatic β-Cells

Type 1 Diabetes is an autoimmune disease leading to beta cell destruction. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to beta cell death in T1D and their target genes remain to be clarified. We performed a miRNA expression profile on human islet preparations exposed to the cytokines IL-1β+IFN-γ. Confirmation of miRNAs and target genes modification in human beta cells was performed by real-time qPCR. Single stranded miRNAs inhibitors were used to block selected endogenous miRNAs. Cell death was measured by Hoechst/propidium iodide staining and activation of caspase-3. Fifty-seven miRNAs were detected as modulated by cytokines. Three of them, namely miR-23a-3p, miR-23b-3p and miR-149-5p, were down-regulated by cytokines and selected for further studies. These miRNAs were found to regulate the expression of the pro-apoptotic Bcl-2 proteins DP5 and PUMA and consequent human beta cell apoptosis. These results identify a novel cross-talk between a key family of miRNAs and pro-apoptotic Bcl-2 proteins in human pancreatic beta cells, broadening our understanding of cytokine-induced beta cell apoptosis in early T1D.