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Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4

Authors
 Inhwa Hwang  ;  Jungmin Yang  ;  Sujeong Hong  ;  Eun Ju Lee  ;  Seung-Hyo Lee  ;  Teresa Fernandes-Alnemri  ;  Emad S Alnemri  ;  Je-Wook Yu 
Citation
 IMMUNOLOGY AND CELL BIOLOGY, Vol.93(6) : 591-599, 2015 
Journal Title
 IMMUNOLOGY AND CELL BIOLOGY 
ISSN
 0818-9641 
Issue Date
2015
MeSH
Animals ; Carrier Proteins/metabolism* ; Caspase 1/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Enzyme Activation/drug effects ; Humans ; Inflammasomes/metabolism* ; Inflammation Mediators/metabolism ; Interleukin-4/metabolism* ; Interleukin-4/pharmacology ; Intracellular Space ; Lipopolysaccharides/immunology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; Protein Binding ; Protein Transport ; Reactive Oxygen Species/metabolism ; STAT6 Transcription Factor/metabolism ; Signal Transduction*/drug effects ; Transcription, Genetic/drug effects
Abstract
Th2 cytokine IL-4 has been previously shown to suppress the production of proinflammatory cytokines in monocytes. However, the underlying molecular mechanism by which IL-4 signaling antagonizes proinflammatory responses is poorly characterized. In particular, whether IL-4 can modulate inflammasome signaling remains unknown. Here, we provide evidence that IL-4 suppresses NLRP3-dependent caspase-1 activation and the subsequent IL-1β secretion but does not inhibit absent in melanoma 2 (AIM2)- or NLRC4 (NOD-like receptor family, CARD domain-containing 4)-dependent caspase-1 activation in THP-1 and mouse bone marrow-derived macrophages. Upon lipopolysaccharide (LPS) or LPS/ATP stimulation, IL-4 markedly inhibited the assembly of NLRP3 inflammasome, including NLRP3-dependent ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) oligomerization, NLRP3-ASC interaction and NLRP3 speck-like oligomeric structure formation. The negative regulation of NLRP3 inflammasome by IL-4 was not due to the impaired mRNA or protein production of NLRP3 and proinflammatory cytokines. Supporting this observation, IL-4 attenuated NLRP3 inflammasome activation even in reconstituted NLRP3-expressing macrophages in which NLRP3 expression is not transcriptionally regulated by TLR-NF-κB signaling. Furthermore, the IL-4-mediated suppression of NLRP3 inflammasome was independent of STAT6-dependent transcription and mitochondrial reactive oxygen species (ROS). Instead, IL-4 inhibited subcellular redistribution of NLRP3 into mitochondria and microtubule polymerization upon NLRP3-activating stimulation. Our results collectively suggest that IL-4 could suppress NLRP3 inflammasome activation in a transcription-independent manner, thus providing an endogenous regulatory machinery to prevent excessive inflammasome activation.
Full Text
http://www.nature.com/icb/journal/v93/n6/full/icb2014125a.html
DOI
10.1038/icb.2014.125
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Hwang, Inhwa(황인화) ORCID logo https://orcid.org/0000-0001-5235-3519
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140552
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