Abstract
Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.
Highlights
The endothelium plays a central role in the pathogenesis of vascular inflammatory diseases such as sepsis (Aird, 2003) and atherosclerosis (Gimbrone & Garcia‐Cardena, 2012; Pober & Sessa, 2007)
The transcription of miR‐146a and miR‐146b was sustained for the duration of IL‐1b treatment. This is in contrast to vascular cell adhesion molecule‐1 (VCAM‐1), SELE (E‐Selectin) and intercellular adhesion molecule‐1 (ICAM‐1) mRNA, which were down‐regulated after 8 h of IL‐1b treatment
Consistent with the reduced levels of phosphorylated ERK (pERK), we found that miR‐ 146a over‐expression inhibited the activation of early growth response (EGR)‐1 and EGR‐3 mRNA in response to IL‐1b, while miR‐146 inhibitors enhanced the induction of EGR‐3 mRNA (Fig 5D)
Summary
The endothelium plays a central role in the pathogenesis of vascular inflammatory diseases such as sepsis (Aird, 2003) and atherosclerosis (Gimbrone & Garcia‐Cardena, 2012; Pober & Sessa, 2007). In addition to feedback regulation at the level of transcription, microRNAs have recently been identified that serve in post‐transcriptional negative feedback loops that modulate inflammatory signalling. MiR‐146a was previously found to be transcriptionally induced by NF‐kB in response to activation of innate immune signalling in monocytes (Taganov et al, 2006). MiR‐146a targets the adaptor proteins TRAF6 and IRAK1/2 (Bhaumik et al, 2008; Hou et al, 2009; Nahid et al, 2009; Taganov et al, 2006) and can inhibit activation of the NF‐kB pathway (Bhaumik et al, 2008; Zhao et al, 2011), suggesting that miR‐146a participates in a negative feedback loop to control NF‐kB signalling in monocytes. The function of miR‐146a/b is poorly understood in endothelial cells
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