Open AccessMicro RNA ‐146 represses endothelial activation by inhibiting pro‐inflammatory pathways
Author(s) -
Cheng Henry S.,
Sivachandran Nirojini,
Lau Andrew,
Boudreau Emilie,
Zhao Jimmy L.,
Baltimore David,
DelgadoOlguin Paul,
Cybulsky Myron I.,
Fish Jason E.
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201202318
Subject(s) - microbiology and biotechnology , inflammation , endothelial activation , enos , signal transduction , endothelium , biology , transcription factor , downregulation and upregulation , chemistry , klf2 , nf κb , nitric oxide synthase , nitric oxide , immunology , gene , biochemistry , genetics , endocrinology
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.