Document Detail

ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury.
MedLine Citation:
PMID:  23408710     Owner:  NLM     Status:  MEDLINE    
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1β (IL-1β), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1β axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1β signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1β antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1β signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-κB)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-κB and ultimately the depression of proinflammatory cytokine programs. Conclusion: ASC-mediated caspase-1/IL-1β signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1β signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR.
Naoko Kamo; Bibo Ke; Amir A Ghaffari; Xiu-da Shen; Ronald W Busuttil; Genhong Cheng; Jerzy W Kupiec-Weglinski
Publication Detail:
Type:  Journal Article     Date:  2013-05-15
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  58     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-26     Completed Date:  2013-08-30     Revised Date:  2014-07-02    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  351-62     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
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MeSH Terms
Caspase 1 / physiology*
Cytoskeletal Proteins / deficiency,  physiology*
HMGB1 Protein / biosynthesis*
Interleukin-1beta / physiology*
Liver / injuries
Mice, Knockout
Reperfusion Injury / immunology*,  prevention & control
Signal Transduction / physiology
Toll-Like Receptor 4 / physiology
Grant Support
Reg. No./Substance:
0/Cytoskeletal Proteins; 0/HMGB1 Protein; 0/HMGB1 protein, mouse; 0/Interleukin-1beta; 0/Pycard protein, mouse; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; EC 1
Comment In:
Hepatology. 2013 Dec;58(6):2212-3   [PMID:  23696070 ]
Hepatology. 2013 Dec;58(6):2212   [PMID:  23696239 ]

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