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标题：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
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作者：Jimmy F. P. Berbée ; Claudia P. Coomans ; Marit Westerterp 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2010
卷号：51
期号：7
页码：1943-1952
DOI：10.1194/jlr.M006809
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Timely sensing of lipopolysaccharide (LPS) is critical for the host to fight invading Gram-negative bacteria. We recently showed that apolipoprotein CI (apoCI) (apoCI_1–57) avidly binds to LPS, involving an LPS-binding motif (apoCI_48–54), 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, apoCI_1–30, and apoCI_35–57 were able to bind LPS, whereas apoCI_1–23 and apoCI_46–57 did not bind LPS. In line with their LPS-binding characteristics, apoCI_1–38, apoCI_1–30, and apoCI_35–57 prolonged the serum residence of ¹²⁵I-LPS by reducing its association with the liver. Accordingly, both apoCI_1–30 and apoCI_35–57 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 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.
关键词：peptide ; inflammation ; endotoxins ; TNFα ; mice