A miR-19 regulon that controls NF-{kappa}B signaling

Michael Paul Marie Gantier, Hilary James Stunden, Claire McCoy, Mark A Behlke, Die Wang, Maria Liaskos, Soroush Sarvestani, Yuan Hang Yang, Dakang Xu, Sinead C Corr, Eric Francis Morand, Bryan Raymond George Williams

Research output: Contribution to journalArticleResearchpeer-review

124 Citations (Scopus)

Abstract

Fine-tuning of inflammatory responses by microRNAs (miRNAs) is complex, as they can both enhance and repress expression of pro-inflammatory mediators. In this study, we investigate inflammatory responses following global miRNA depletion, to better define the overall contribution of miRNAs to inflammation. We demonstrate that miRNAs positively regulate Toll-like receptor signaling using inducible Dicer1 deletion and global miRNA depletion. We establish an important contribution of miR-19b in this effect, which potentiates nuclear factor-kappaB (NF-kappaB) activity in human and mouse cells. Positive regulation of NF-kappaB signaling by miR-19b involves the coordinated suppression of a regulon of negative regulators of NF-kappaB signaling (including A20/Tnfaip3, Rnf11, Fbxl11/Kdm2a and Zbtb16). Transfection of miR-19b mimics exacerbated the inflammatory activation of rheumatoid arthritis primary fibroblast-like synoviocytes, demonstrating its physiological importance in the pathology of this disease. This study constitutes, to our knowledge, the first description of a miR-19 regulon that controls NF-kappaB signaling, and suggests that targeting this miRNA and linked family members could regulate the activity of NF-kappaB signaling in inflammation.
Original languageEnglish
Pages (from-to)8048 - 8058
Number of pages11
JournalNucleic Acids Research
Volume40
Issue number16
DOIs
Publication statusPublished - 2012

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