Document Detail

The alarmin cytokine, high mobility group box 1, is produced by viable cardiomyocytes and mediates the lipopolysaccharide-induced myocardial dysfunction via a TLR4/phosphatidylinositol 3-kinase gamma pathway.
MedLine Citation:
PMID:  20028656     Owner:  NLM     Status:  MEDLINE    
High mobility group box 1 (HMGB1) is an alarmin actively secreted by immune cells and passively released by necrotic nonimmune cells. HMGB1 has been implicated in both cardiac contractile dysfunction and the lethality associated with sepsis/endotoxemia. The aim of the current study was to assess whether viable cardiomyocytes could produce HMGB1 and whether HMGB1 can affect myocardial contractility. LPS was used as a model of sepsis/endotoxemia in mice and isolated cardiac myocytes. LPS increased myocardial expression of HMGB1 in vivo (immunohistochemistry) and production and secretion of HMGB1 by viable cardiac myocytes in vitro (Western). LPS increased the phosphorylation status of PI3Kgamma in cardiac myocytes, an effect not observed in TLR4(-/-) myocytes. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced 1) cardiomyocyte production and secretion of HMGB1 in vitro and 2) HMGB1 expression in the myocardium in vivo. The LPS-induced depression of myocardial contractility was prevented by the HMGB1 antagonist, A-box. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced decrease in myocardial contractility. No evidence of inflammatory infiltrate was noted in any of the in vivo studies. The findings of the current study indicate that 1) LPS can induce HMGB1 secretion by viable cardiac myocytes through a TLR4/PI3Kgamma signaling pathway, and 2) HMGB1 plays a role in the LPS-induced myocardial contractile dysfunction. The results of the current study also have broader implications (i.e., that viable parenchymal cells, such as cardiac myocytes, participate in the alarmin response).
Hu Xu; Zhaoliang Su; Jun Wu; Min Yang; Josef M Penninger; Claudio M Martin; Peter R Kvietys; Tao Rui
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-18
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  184     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-21     Completed Date:  2010-03-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1492-8     Citation Subset:  AIM; IM    
Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / deficiency,  genetics,  physiology*
Animals, Newborn
Cardiomyopathies / enzymology,  immunology*,  physiopathology
Cell Survival / immunology
Cells, Cultured
Cytokines / biosynthesis*,  physiology,  secretion
Disease Models, Animal
Endotoxemia / enzymology,  immunology,  physiopathology
HMGB1 Protein / biosynthesis*,  physiology,  secretion
Isoenzymes / deficiency,  genetics,  physiology
Lipopolysaccharides / toxicity
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction / genetics,  immunology
Myocytes, Cardiac / immunology*,  metabolism*,  secretion
Signal Transduction / genetics,  immunology*
Toll-Like Receptor 4 / deficiency,  genetics,  physiology*
Grant Support
MOP-81303//Canadian Institutes of Health Research
Reg. No./Substance:
0/Cytokines; 0/HMGB1 Protein; 0/Isoenzymes; 0/Lipopolysaccharides; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; EC 3-Kinase; EC 3-kinase gamma

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