1. Glucocorticoids downregulate TLR4 signaling activity via its direct targeting by miR-511-5p.
- Author
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Curtale G, Renzi TA, Drufuca L, Rubino M, and Locati M
- Subjects
- Cell Line, Tumor, Cells, Cultured, Dexamethasone pharmacology, Flow Cytometry, Gene Expression Regulation drug effects, HEK293 Cells, Humans, Interleukin-12 Subunit p40 genetics, Interleukin-12 Subunit p40 metabolism, Lipopolysaccharides pharmacology, Monocytes drug effects, Monocytes metabolism, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 4 metabolism, Transforming Growth Factor beta pharmacology, Down-Regulation drug effects, Glucocorticoids pharmacology, MicroRNAs genetics, Signal Transduction drug effects, Toll-Like Receptor 4 genetics
- 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., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2017
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