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Sci Rep
2018[Jul]; 8
(1
): 11367
PMID30054544
show ga
Endotoxin tolerance is a phenomenon characterized by a reduced capacity of
monocytes and macrophages to respond to repeated stimulation with
lipopolysaccharide (LPS) which has been suggested to represent a way of
controlling the intensity and duration of innate immune response. During
endotoxin tolerance, monocytes undergo functional re-programming primarily by
epigenetic regulation. Recently, micro-RNA (miR)-146a has been demonstrated to be
the major player of the negative regulation of the pro-inflammatory response,
affecting TNF-? production. In this study, we have employed CyP, a cyanobacterial
LPS antagonist acting on TLR4-MD2 complex, for priming human monocytes and
evaluating their response to a subsequent challenge with E. coli LPS. Results
show that CyP is able to induce cross-tolerance to E. coli LPS by inhibiting
TNF-? production. The mechanism of action is mediated by a specific induction of
miR-146a and reduction of IRAK1 and TRAF6 expressions in human monocytes by CyP
priming. Up-regulation of miR-146a by CyP alone, affects subsequent cell response
in term of TNF-? production even when monocytes are incubated with other TLR
ligands, as lipoteichoic acid (LTA), thus confirming miR-146a as a critical
player mediating TNF-? regulation during cross-tolerance with CyP.
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