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Glucocorticoids downregulate TLR4 signaling activity via its direct targeting by miR‐511‐5p
Author(s) -
Curtale Graziella,
Renzi Tiziana A.,
Drufuca Lorenzo,
Rubino Marcello,
Locati Massimo
Publication year - 2017
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201747044
Subject(s) - tlr4 , biology , mediator , inflammation , microbiology and biotechnology , downregulation and upregulation , signal transduction , microrna , intracellular , immunology , gene , biochemistry
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.