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

TLDR

Innate and adaptive immune responses are tightly regulated by complex mechanisms, and microRNAs act as negative post‑transcriptional regulators of key adapter proteins such as TRAF6 and IRAK1 downstream of Toll‑like and cytokine receptors. The study aims to demonstrate that miR‑146 regulates Toll‑like receptor and cytokine signaling by down‑regulating IRAK1 and TRAF6 through a negative feedback loop. The authors predicted miR‑146a/b binding to the 3′UTRs of TRAF6 and IRAK1 and confirmed that these UTRs suppress reporter gene expression. miR‑146a/b are endotoxin‑responsive, NF‑kappaB‑dependent microRNAs that target the 3′UTRs of TRAF6 and IRAK1, thereby inhibiting their expression.

Abstract

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-kappaB-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.