MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage. / Vestergaard, Anna Lindelov; Bang-Berthelsen, Claus Heiner; Floyel, Tina; Stahl, Jonathan Lucien; Christen, Lisa; Sotudeh, Farzaneh Taheri; Horskjaer, Peter de Hemmer; Frederiksen, Klaus Stensgaard; Kofod, Frida Greek; Bruun, Christine; Berchtold, Lukas Adrian; Storling, Joachim; Regazzi, Romano; Kaur, Simranjeet; Pociot, Flemming; Mandrup-Poulsen, Thomas.
In: PLOS ONE, Vol. 13, No. 9, e0203713 , 27.09.2018, p. 1-22.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage
AU - Vestergaard, Anna Lindelov
AU - Bang-Berthelsen, Claus Heiner
AU - Floyel, Tina
AU - Stahl, Jonathan Lucien
AU - Christen, Lisa
AU - Sotudeh, Farzaneh Taheri
AU - Horskjaer, Peter de Hemmer
AU - Frederiksen, Klaus Stensgaard
AU - Kofod, Frida Greek
AU - Bruun, Christine
AU - Berchtold, Lukas Adrian
AU - Storling, Joachim
AU - Regazzi, Romano
AU - Kaur, Simranjeet
AU - Pociot, Flemming
AU - Mandrup-Poulsen, Thomas
PY - 2018/9/27
Y1 - 2018/9/27
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0203713
DO - 10.1371/journal.pone.0203713
M3 - Journal article
C2 - 30260972
VL - 13
SP - 1
EP - 22
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 9
M1 - e0203713
ER -
ID: 210015663