MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage.

Details

Ressource 1Download: journal.pone.0203713.pdf (3564.56 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_24D77AE6DEBA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage.
Journal
PloS one
Author(s)
Lindeløv Vestergaard A., Heiner Bang-Berthelsen C., Fløyel T., Lucien Stahl J., Christen L., Taheri Sotudeh F., de Hemmer Horskjær P., Stensgaard Frederiksen K., Greek Kofod F., Bruun C., Adrian Berchtold L., Størling J., Regazzi R., Kaur S., Pociot F., Mandrup-Poulsen T.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
13
Number
9
Pages
e0203713
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
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.
Keywords
Adult, Animals, Apoptosis, Cell Line, Cytokines/metabolism, Diabetes Mellitus/genetics, Diabetes Mellitus/metabolism, Female, Gene Expression Regulation, Histone Deacetylase Inhibitors/pharmacology, Humans, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/physiology, Islets of Langerhans/metabolism, Male, MicroRNAs/physiology, Middle Aged, NF-kappa B/genetics, NF-kappa B/metabolism, Rats, Rats, Wistar
Pubmed
Web of science
Open Access
Yes
Create date
25/10/2018 13:11
Last modification date
20/08/2019 13:03
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