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

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.

RETRACTED: Overexpression of MicroRNA-340-5p Inhibits Pulmonary Arterial Hypertension Induced by APE by Downregulating IL-1β and IL-6

“… 13 Meanwhile, miR-340-5p has been found to mediate IL-1β. 14 IL-1β and IL-6 are proinflammatory cytokines that are associated with chronic or increased inflammation. 15 Evidence has been presented, suggesting that the upregulation of IL-1β is correlated with APE.…”

Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity

“…Accumulated nitrite from cell supernatants was quantified by the Griess reagent assay as a proxy for NO production as described in [ 90 ].…”

Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes

“…Beta cell microRNAs (miRs) are also implicated in islet inflammation and associated with IL signaling [40][41][42]. Pro-inflammatory mediators induced miR-146a-5p expression in human islets, MIN6 mouse beta cells and INS1 rat beta cells [41,43,44], to adapt to IL1β-mediated NFκB activation (as there are NFκB binding elements on the miR-146a promoter [41,45,46]). In INS1 cells transfected with miR-146a-5p, there was reduced NFκB and inducible nitric oxide synthase (iNOS) promotor activity that subsequently decreased cytokine-mediated iNOS protein expression, nitic oxide (NO) synthesis and mitogen-activated protein kinase (MAPK) signaling [44].…”

“…In INS1 cells transfected with miR-146a-5p, there was reduced NFκB and inducible nitric oxide synthase (iNOS) promotor activity that subsequently decreased cytokine-mediated iNOS protein expression, nitic oxide (NO) synthesis and mitogen-activated protein kinase (MAPK) signaling [44]. Therefore, miR-146a-5p down-regulated islet inflammation and beta cell death by impairing NFκB and MAPK signaling [44].…”