caa a22 4500 530216833 CHVBK 20190303135102.0 cr unu---uuuuu 181027s2018 xx s 000 0 eng 10.1371/journal.pone.0203713 doi (SERVAL)BIB_24D77AE6DEBA 30260972 pmid 000445907400015 isiid MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage [Elektronische Daten] [A. Lindeløv Vestergaard, C. Heiner Bang-Berthelsen, T. Fløyel, J. Lucien Stahl, L. Christen, F. Taheri Sotudeh, P. de Hemmer Horskjær, K. Stensgaard Frederiksen, F. Greek Kofod, C. Bruun, L. Adrian Berchtold, J. Størling, R. Regazzi, S. Kaur, F. Pociot, T. Mandrup-Poulsen] Inflammatory β-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Pro-inflammatory cytokines cause β-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent β-cell failure in vitro and in vivo, in part by reducing NF-κB transcriptional activity. We investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat, prior to exposure to the pro-inflammatory cytokines IL-1β and IFN-γ for 6 h or 24 h, and miR expression was profiled with miR array. Thirteen miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, miR-455-5p, miR-466b-2-3p, miR-652-5p, and miR-3584-5p) were regulated by both cytokines and Givinostat, and nine were examined by qRT-PCR. miR-146a-5p was strongly regulated by cytokines and KDACi and was analyzed further. miR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced cytokine signaling, including the activity of NF-κB and iNOS promoters, as well as NO production and protein levels of iNOS and its own direct targets TNF receptor associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). miR-146a-5p was elevated in the pancreas of diabetes-prone BB-DP rats at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced β-cell apoptosis, demonstrating the strength of this approach. Lindeløv Vestergaard A. aut Heiner Bang-Berthelsen C. aut Fløyel T. aut Lucien Stahl J. aut Christen L. aut Taheri Sotudeh F. aut de Hemmer Horskjær P. aut Stensgaard Frederiksen K. aut Greek Kofod F. aut Bruun C. aut Adrian Berchtold L. aut Størling J. aut Regazzi R. aut Kaur S. aut Pociot F. aut Mandrup-Poulsen T. aut PloS one 13/9(2018), e0203713 13:9<e0203713 2018 13 1 article serval SERVAL 700 1- Lindeløv Vestergaard A. aut SERVAL 700 1- Heiner Bang-Berthelsen C. aut SERVAL 700 1- Fløyel T. aut SERVAL 700 1- Lucien Stahl J. aut SERVAL 700 1- Christen L. aut SERVAL 700 1- Taheri Sotudeh F. aut SERVAL 700 1- de Hemmer Horskjær P. aut SERVAL 700 1- Stensgaard Frederiksen K. aut SERVAL 700 1- Greek Kofod F. aut SERVAL 700 1- Bruun C. aut SERVAL 700 1- Adrian Berchtold L. aut SERVAL 700 1- Størling J. aut SERVAL 700 1- Regazzi R. aut SERVAL 700 1- Kaur S. aut SERVAL 700 1- Pociot F. aut SERVAL 700 1- Mandrup-Poulsen T. aut SERVAL 773 0- PloS one 13/9(2018), e0203713 13:9<e0203713 2018 13 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article