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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Anna Lindelov Vestergaard
  • Claus Heiner Bang-Berthelsen
  • Tina Floyel
  • Stahl-Meyer, Jonathan
  • Lisa Christen
  • Farzaneh Taheri Sotudeh
  • Peter de Hemmer Horskjaer
  • Klaus Stensgaard Frederiksen
  • Frida Greek Kofod
  • Christine Bruun
  • Lukas Adrian Berchtold
  • Joachim Storling
  • Romano Regazzi
  • Simranjeet Kaur
  • Pociot, Flemming
  • Mandrup-Poulsen, Thomas

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.

OriginalsprogEngelsk
Artikelnummere0203713
TidsskriftPLOS ONE
Vol/bind13
Udgave nummer9
Sider (fra-til)1-22
Antal sider22
ISSN1932-6203
DOI
StatusUdgivet - 27 sep. 2018

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