Document Detail


Apolipoprotein CI enhances the biological response to LPS via the CD14/TLR4 pathway by LPS-binding elements in both its N- and C-terminal helix.
MedLine Citation:
PMID:  20335569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Timely sensing of lipopolysaccharide (LPS) is critical for the host to fight invading Gram-negative bacteria. We recently showed that apolipoprotein CI (apoCI) (apoCI1-57) avidly binds to LPS, involving an LPS-binding motif (apoCI48-54), and thereby enhances the LPS-induced inflammatory response. Our current aim was to further elucidate the structure and function relationship of apoCI with respect to its LPS-modulating characteristics and to unravel the mechanism by which apoCI enhances the biological activity of LPS. We designed and generated N- and C-terminal apoCI-derived peptides containing varying numbers of alternating cationic/hydrophobic motifs. ApoCI1-38, apoCI1-30, and apoCI35-57 were able to bind LPS, whereas apoCI1-23 and apoCI46-57 did not bind LPS. In line with their LPS-binding characteristics, apoCI1-38, apoCI1-30, and apoCI35-57 prolonged the serum residence of 125I-LPS by reducing its association with the liver. Accordingly, both apoCI1-30 and apoCI35-57 enhanced the LPS-induced TNFalpha response in vitro (RAW 264.7 macrophages) and in vivo (C57Bl/6 mice). Additional in vitro studies showed that the stimulating effect of apoCI on the LPS response resembles that of LPS-binding protein (LBP) and depends on CD14/ Toll-like receptor 4 signaling. We conclude that apoCI contains structural elements in both its N-terminal and C-terminal helix to bind LPS and to enhance the proinflammatory response toward LPS via a mechanism similar to LBP.
Authors:
Jimmy F P Berbée; Claudia P Coomans; Marit Westerterp; Johannes A Romijn; Louis M Havekes; Patrick C N Rensen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-24
Journal Detail:
Title:  Journal of lipid research     Volume:  51     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-11     Completed Date:  2010-10-18     Revised Date:  2011-08-01    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1943-52     Citation Subset:  IM    
Affiliation:
Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. J.F.P.Berbee@lumc.nl
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antigens, CD14 / immunology*
Apolipoprotein C-I / chemistry*,  genetics,  immunology*
Cell Line
Lipopolysaccharides* / immunology,  pharmacology
Macrophages / cytology,  drug effects,  immunology
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Sequence Data
Peptides / chemistry,  genetics,  immunology
Protein Binding
Protein Structure, Secondary*
Sequence Alignment
Signal Transduction / immunology*
Toll-Like Receptor 4 / immunology*
Tumor Necrosis Factor-alpha / immunology
Chemical
Reg. No./Substance:
0/Antigens, CD14; 0/Apolipoprotein C-I; 0/Lipopolysaccharides; 0/Peptides; 0/Toll-Like Receptor 4; 0/Tumor Necrosis Factor-alpha
Comments/Corrections

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