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
article
Timely sensing of lipopolysaccharide (LPS) is critical for the host to fight invading Gram-negative bacteria. We recently showed that apolipoprotein CI (apoCI) (apoCI<sub>1-57</sub>) avidly binds to LPS, involving an LPS-binding motif (apoCI<sub>48-54</sub>), 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 <sub>1-38</sub>, apoCI<sub>1-30</sub>, and apoCI<sub>35-57</sub> were able to bind LPS, whereas apoCI<sub>1-23</sub> and apoCI<sub>46-57</sub> did not bind LPS. In line with their LPS-binding characteristics, apoCI<sub>1-38</sub>, apoCI<sub>1-30</sub>, and apoCI<sub>35-57</sub> prolonged the serum residence of <sup>125</sup>I-LPS by reducing its association with the liver. Accordingly, both apoCI<sub>1-30</sub> and apoCI<sub>35-57</sub> enhanced the LPS-induced TNFα 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.<sup>jlr</sup> 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.
Topics
Biomedical ResearchEndotoxinsInflammationMicePeptideTnfαApolipoprotein C1CD14 antigenLipopolysaccharideLipopolysaccharide binding proteinToll like receptor 4Tumor necrosis factor alphaAmino terminal sequenceAnimal cellAnimal experimentCarboxy terminal sequenceControlled studyCytokine releaseElectrophoretic mobilityMouseNonhumanPeritoneum macrophagePlasma clearanceSignal transduction
TNO Identifier
364397
ISSN
00222275
Source
Journal of Lipid Research, 51(7), pp. 1943-1952.
Pages
1943-1952