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2016 ; 6
(ä): 25013
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p58(IPK) suppresses NLRP3 inflammasome activation and IL-1? production via
inhibition of PKR in macrophages
#MMPMID27113095
Boriushkin E
; Wang JJ
; Li J
; Bhatta M
; Zhang SX
Sci Rep
2016[Apr]; 6
(ä): 25013
PMID27113095
show ga
The NLRP3 inflammasome activation is a key signaling event for activation and
secretion of pro-inflammatory cytokines such as IL-1? from macrophages. p58(IPK)
is a molecular chaperone that regulates protein homeostasis through inhibiting
eIF-2? kinases including double-stranded RNA-dependent protein kinase (PKR),
which has been recently implicated in inflammasome activation. Herein we
investigate the role of p58(IPK) in TLR4 signaling and inflammasome activation in
macrophages. Primary bone marrow-derived macrophages (BMDM) was isolated from
p58(IPK) knockout (KO) and wildtype (WT) mice and treated with lipopolysaccharide
(LPS) and ATP to activate TLR4 signaling and stimulate inflammasome activation.
Compared to WT macrophages, p58(IPK) deficient cells demonstrated significantly
stronger activation of PKR, NF-?B, and JNK and higher expression of
pro-inflammatory genes TNF-? and IL-1?. Coincidently, p58(IPK) deletion
intensified NLRP3-inflammasome activation indicated by enhanced caspase 1
cleavage and increased IL-1? maturation and secretion. Pretreatment with specific
PKR inhibitor or overexpression of p58(IPK) largely abolished the changes in
inflammasome activation and IL-1? secretion in p58(IPK) null macrophages.
Furthermore, immunoprecipitation assay confirmed the binding of p58(IPK) with
PKR, but not other TLR4 downstream signaling molecules. Collectively, these
results suggest a novel and crucial role of p58(IPK) in regulation of
inflammasome activation and IL-1? secretion in macrophages.