Document Detail


Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice.
MedLine Citation:
PMID:  23460269     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, Toll-like receptor (TLR)4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and nonimmune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically, parenchymal hepatocytes (HCs), myeloid cells, including Kupffer cells, and dendritic cells (DCs) subsequent to hepatic I/R. When HC-specific (Alb-TLR4(-/-) ) and myeloid-cell-specific (Lyz-TLR4(-/-) ) TLR4 knockout (KO) mice were subjected to warm hepatic ischemia, there was significant protection in these mice, compared to wild type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 KO (TLR4(-/-) ) mice. DC-specific TLR4(-/-) (CD11c-TLR4(-/-) ) mice had significantly increased hepatocellular damage, compared to WT mice. Circulating levels of high-mobility group box 1 (HMGB1) were significantly reduced in Alb-TLR4(-/-) mice, compared to WT, Lyz-TLR4(-/-) , CD11c-TLR4(-/-) mice and equivalent to global TLR4(-/-) mice, suggesting that TLR4-mediated HMGB1 release from HCs may be a source of HMGB1 after I/R. HCs exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases, c-Jun-N-terminal kinase (JNK) and p38, in a TLR4-dependent manner; inhibition of JNK decreased release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion: These results provide insight into the individual cellular response of TLR4. The parenchymal HC is an active participant in sterile inflammatory response after I/R through TLR4-mediated activation of proinflammatory signaling and release of danger signals, such as HMGB1.
Authors:
Gary W Nace; Hai Huang; John R Klune; Raymond E Eid; Brian R Rosborough; Sebastian Korff; Shen Li; Richard A Shapiro; Donna B Stolz; Chhinder P Sodhi; David J Hackam; David A Geller; Timothy R Billiar; Allan Tsung
Related Documents :
24252149 - Induction of cns α-synuclein pathology by fibrillar and non-amyloidogenic recombinant ...
23300459 - Irf-3, irf-5, and irf-7 coordinately regulate the type i ifn response in myeloid dendri...
22977259 - Delayed cutaneous wound healing in fam129b/minerva-deficient mice.
23223089 - Mineralocorticoid receptor blockade inhibits accelerated atherosclerosis induced by a l...
24652469 - Interruption of classic cd40l-cd40 signalling but not of the novel cd40l-mac-1 interact...
23184679 - Blockade of myd88 signaling induces antitumor effects by skewing the immunosuppressive ...
11681809 - Pro-inflammatory cytokines and adipose tissue.
8764139 - Tyrosine kinase inhibitors prevent cytokine-induced expression of inos and cox-2 by hum...
9083279 - Increased expression of decorin in experimental hydronephrosis.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-05-27
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:  374-87     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Dendritic Cells / immunology
HMGB1 Protein / secretion
Hepatocytes / immunology*
Immunity, Innate / physiology*
JNK Mitogen-Activated Protein Kinases / metabolism
Kupffer Cells / immunology
Liver / immunology*
Male
Mice
Mice, Knockout
Myeloid Cells / immunology
Reperfusion Injury / immunology*
Toll-Like Receptor 4 / deficiency,  physiology*
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
ID/Acronym/Agency:
P50 GM053789/GM/NIGMS NIH HHS; R01 DK083752/DK/NIDDK NIH HHS; R01 GM050441/GM/NIGMS NIH HHS; R01 GM078238/GM/NIGMS NIH HHS; R01 GM095566/GM/NIGMS NIH HHS; R01-GM50441/GM/NIGMS NIH HHS; R01-GM95566/GM/NIGMS NIH HHS; T32 AI074490/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/HMGB1 Protein; 0/HMGB1 protein, mouse; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Differential nuclear organization of translocation-prone genes in nonmalignant B cells from patients...
Next Document:  Charles Bonnet syndrome in cranio-maxillofacial surgery: case report.