Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals

Abstract

Inflammation involves a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanisms. Recent studies have shown that microRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide noncoding RNAs, contribute to the regulation of inflammation by repressing gene expression at the posttranscriptional level. In this study, we characterize the profile of miRNAs induced by LPS in human polymorphonuclear neutrophils (PMN) and monocytes. In particular, we identify miR-9 as the only miRNA (among 365 analyzed) up-regulated in both cell types after TLR4 activation. miR-9 is also induced by TLR2 and TLR7/8 agonists and by the proinflammatory cytokines TNF-␣ and IL-1␤, but not by IFN␥. Among the 3 different genes encoding miR-9 precursors in humans, we show that LPS selectively induces the transcription of miR-9 -1 located in the CROC4 locus, in a MyD88-and NF-B-dependent manner. In PMN and monocytes, LPS regulates NFKB1 at both the transcriptional and posttranscriptional levels, and a conserved miR-9 seed sustained a miR-9-dependent inhibition of the NFKB1 transcript. Overall, these data suggest that TLR4-activated NF-B rapidly increases the expression of miR-9 that operates a feedback control of the NF-B-dependent responses by fine tuning the expression of a key member of the NF-B family.inflammation ͉ innate immunity ͉ Toll-like receptors ͉ cytokines ͉ NFKB1

The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade

“…This observation is also supported by the report that the miR-9 family is specifically hypermethylated in metastatic cancers [107]. Downregulation of the miR-9 family members is shown to activate NF-kappaB1, recruit DNA methyltransferase 1 and increase in DNA methylation [125][126][127]. Lastly, expression of the proangiogenic miR-210 (Table 1), a hypoxia-induced miRNA [24,43,44], has been shown to increase metastatic capability in both breast and pancreatic cancers [119,128].…”

MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling

“…These data suggest that the acquisition of SASP during replicative senescence is not fully controlled by miR-146a. Further studies are in progress to clarify the role of the other three upregulated miRs in senescent cells, involved both in the TLR pathway and inflammatory response (Bazzoni et al 2009;Li et al 2011).…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…MiR-9, the TLR-responsive miRNA, is shown to directly target Nfkb1 mRNA. 62 NFKB1 is the NF-kB p50 subunit precursor, which acts to transactivate the NF-kB p65 subunit. Thus, TLR agonists induce miR-9 in a MyD88/NF-kB-dependent pathway, while miR-9-mediated feedback controls NF-kB responses by fine-tuning the expression of a key NFkB family member.…”

“…Thus, TLR agonists induce miR-9 in a MyD88/NF-kB-dependent pathway, while miR-9-mediated feedback controls NF-kB responses by fine-tuning the expression of a key NFkB family member. 62 More recently, miR-210 has also been demonstrated to be induced by LPS and target Nfkb1 mRNA. 84 Other transcription factors downstream of the TLR signaling pathway have been identified as miRNA targets.…”

“…52 Other miRNAs are also induced after TLR treatment or pathogen infection, including miR-223, miR-147, miR-9, miR-27b and let7e. [60][61][62][63] While the upregulation of these miRNAs by TLR activation has been identified to be mostly dependent on de novo primary miRNA transcription by certain transcription factors, we cannot exclude the possibility that the accelerated processing of primary miRNA/precursor miRNA or the retarded degradation of mature miRNA also results in increased miRNA concentration. For the most part, primary miRNA transcription is dependent on the NF-kB transcription factor.…”