Glucocorticoids downregulate TLR4 signaling activity via its direct targeting by miR-511-5p

Graziella Curtale, Tiziana A. Renzi, Lorenzo Drufuca, Marcello Rubino, Massimo Locati

Research output: Contribution to journalArticlepeer-review

Abstract

Endotoxin tolerance assures proper regulation of the TLR4 signaling pathway and avoids uncontrolled inflammation, limiting tissue damage and endotoxin shock development. Though underlying molecular mechanisms are still undefined, evidence indicates the involvement of microRNAs, which represent a new layer of regulation of inflammatory pathways. Here, we report that LPS and other inflammatory stimuli repress miR-511-5p expression in human monocytes, while anti-inflammatory stimuli, such as TGF-β and glucocorticoids, have the opposite effect. MiR-511-5p levels selectively influenced cell activation when endotoxin was used, while biological activity of other TLR agonists was unaffected. Consistent with this, TLR4 was validated as the miR-511-5p direct target responsible for glucocorticoids- and TGF-β-mediated inhibition of pro-inflammatory cytokines production observed in endotoxin tolerant monocytes. MiR-511-5p thus acts as an intracellular mediator of glucocorticoids and TGF-β for the induction of endotoxin tolerance in human monocytes.

Original languageEnglish
Pages (from-to)2080-2089
Number of pages10
JournalEuropean Journal of Immunology
Volume47
Issue number12
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • Endotoxin tolerance
  • Inflammation
  • Macrophage
  • microRNA
  • miR-511-5p

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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