NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

KD Taganov, MP Boldin, KJ Chang… - Proceedings of the …, 2006 - National Acad Sciences
KD Taganov, MP Boldin, KJ Chang, D Baltimore
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
Activation of mammalian innate and acquired immune responses must be tightly regulated
by elaborate mechanisms to control their onset and termination. MicroRNAs have been
implicated as negative regulators controlling diverse biological processes at the level of
posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes
revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-
responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern …
Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-κB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3′ UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.
National Acad Sciences