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Myeloid-related protein 8 induces self-tolerance and cross-tolerance to bacterial
infection via TLR4- and TLR2-mediated signal pathways
#MMPMID26329314
Coveney AP
; Wang W
; Kelly J
; Liu JH
; Blankson S
; Wu QD
; Redmond HP
; Wang JH
Sci Rep
2015[Sep]; 5
(?): 13694
PMID26329314
show ga
Myeloid-related protein 8 (Mrp8) is the active component of Mrp8/14 protein
complex released by phagocytes at the site of infection and stimulates
inflammatory responses. However, it is unclear whether Mrp8 could induce
self-tolerance and cross-tolerance to bacterial infection. Here we report that
Mrp8 triggered TNF-? and IL-6 release via a Toll-like receptor 4 (TLR4)-dependent
manner. Pre-stimulation of murine macrophages and human monocytes with Mrp8
induced self-tolerance to Mrp8 re-stimulation and cross-tolerance to
lipopolysaccharide (LPS), bacterial lipoprotein (BLP), gram-negative and
gram-positive bacterial challenges, with substantially attenuated TNF-? and IL-6
release. Moreover, Mrp8 tolerisation significantly reduced serum TNF-? and IL-6,
increased polymorphonuclear neutrophil (PMN) recruitment and accelerated
bacterial clearance, thus protecting mice against LPS-induced lethality and cecal
ligation and puncture (CLP)-induced polymicrobial sepsis. In addition to TLR4,
TLR2 also contributed to Mrp8-induced inflammatory response and tolerance.
Down-regulation of phosphorylated p38 by Mrp8 pre-stimulation was predominantly
responsible for the intracellular mechanism of Mrp8-induced tolerance. Thus, our
findings of Mrp8-induced self-tolerance and cross-tolerance may provide a
potential strategy for attenuating an overwhelming proinflammatory cascade and
enhancing antimicrobial responses during microbial sepsis.
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