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

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 I-125-LPS by reducing its association with the liver. Accordingly, both apoCI(1-30) and apoCI(35-57) enhanced the LPS-induced TNF alpha 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.(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.-Berbee, J. F. P., C. P. Coomans, M. Westerterp, J. A. Romijn, L. M. Havekes, and P. C. N. Rensen. 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. J. Lipid Res. 2010. 51: 1943-1952