Title
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
Author
TNO Kwaliteit van Leven
Berbé, J.F.P.
Coomans, C.P.
Westerterp, M.
Romijn, J.A.
Havekes, L.M.
Rensen, P.C.N.
Publication year
2010
Abstract
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. ApoCI 1-38, 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 LPSbinding protein (LBP) and depends on CD14/ Toll-like receptor 4 signaling.jlr 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. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.
Subject
Biomedical Research
Endotoxins
Inflammation
Mice
Peptide
Tnfalpha
Apolipoprotein C1
CD14 antigen
Lipopolysaccharide
Lipopolysaccharide binding protein
Toll like receptor 4
Tumor necrosis factor alpha
Amino terminal sequence
Animal cell
Animal experiment
Carboxy terminal sequence
Controlled study
Cytokine release
Electrophoretic mobility
Mouse
Nonhuman
Peritoneum macrophage
Plasma clearance
Signal transduction
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http://resolver.tudelft.nl/uuid:01477352-f3d8-4f0e-a7b2-d0ca6cc90052
TNO identifier
364397
ISSN
0022-2275
Source
Journal of Lipid Research, 51 (51), 1943-1952
Document type
article