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Researchers ID miRNA Involved in Innate Immune Response

NEW YORK (GenomeWeb News) – In a paper that appeared online last night in the Proceedings of the National Academy of Sciences, an Italian research team identified a miRNA that appears to be involved in the innate immune response by helping to regulate cellular responses that depend on the transcription factor complex NF-kappa-B.

The researchers assessed miRNA levels in two types of human immune cells — monocytes and polymorphonuclear neutrophils — exposed to inflammation-stimulating bacterial lipopolysaccharides or LPS for several hours. Although more than a dozen miRNAs were up-regulated in either human monocytes or PMN following LPS exposure, the team found just one that was up-regulated in both: miR-9. Based on their subsequent experiments, they propose that miR-9 targets the NF-kappa-B sub-unit NFKB1 tempering the NF-kappa-B-dependent immune response.

In contrast to adaptive immunity, which "remembers" infectious agents from previous exposure, innate immunity provides first-line protection against infectious agents. For instance, the components of the innate immune system can use inflammation and phagocytosis to get rid of cellular debris and/or pathogens that enter the body.

Since microRNAs, a group of 22-nucleotide, non-protein coding regulatory RNAs, have been implicated in everything from development to immunity to tumor formation, senior author Massimo Locati, a researcher at the University of Milan's Department of Translational Medicine, and his team decided to look at the miRNAs involved in human innate cell response to bacterial LPS.

Specifically, the researcher used a TaqMan-based low density array to assess miRNAs in two types of innate immune cells — PMN and monocytes — that had been stimulated with LPS for eight hours.

Their search turned up a dozen miRNAs that were up-regulated in one of the cell types. But when the team used RT-qPCR time course analyses to follow up on their initial experiments they found that just one miRNA — miR-9 — was up-regulated in both PMN and monocytes. Their subsequent experiments suggest adding LPS triggers miR-9 induction via an immune pathway containing the adaptor protein MyD88 and NF-kappa-B.

Although miR-9 precursors are encoded by three different genes: Clorf61, BC036480, and CR612213, the researchers found that LPS treatment only ramped up the level of pri-miR-9-1, the primary transcript encoded by Clorf61.

Next, the team looked for miR-9 targets using miRGen, a public database of animal miRNAs and their predicted targets. They found potential miR-9 targets in the transcription regulators Onecut2 and PRDM1/Blimp-1. But since neither regulator is expressed in the two cell types tested, though, the researchers instead focused on another potential miR-9 target: NFKB1, which codes for the NF-kappa-B p50 subunit and its precursor p105.

Consistent with this, the researchers demonstrated that miR-9 curbs NF-kappa-B activity. In addition, their research suggests that, while more NFKB1 transcripts are present in LPS-stimulated PMN and monocytes, there is no comparable rise in NFKB1 protein products. That, in turn, suggests post-transcriptional regulation of the gene, possibly by miR-9.

Overall, the researchers concluded that miR-9 — previously shown to influence neuronal development and function in the mammalian brain and to regulate insulin- and B-cell related transcription factors outside the central nervous system — has a role in tweaking NF-kappa-B levels during the pro-inflammatory phase of innate immunity.

"Since [NF-kappa-B] is a key regulator of inflammation, the [NF-kappa-B] levels are likely to be a strictly controlled and timely regulated event of relevance for the proper progression of the inflammatory response," the authors wrote.

"On the basis of our observations it is tempting to propose a model in which the parallel [NF-kappa-B]-dependent induction of NFKB1 and miR-9 provides a mean to smooth out the fluctuations in gene expression and fine tune the synthesis of this key transcription factor, thus allowing the pro-inflammatory phase of the LPS response to correctly proceed."

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