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) (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 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.
