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
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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DOI：
10.1194/jlr.m006809
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发表时间：
2010-07-01
影响因子：
6.5
通讯作者：
Rensen, Patrick C. N.
中科院分区：
文献类型：
--
作者：
Berbee, Jimmy F. P.;Coomans, Claudia P.;Rensen, Patrick C. N.
及时感知内毒素对宿主对抗入侵的革兰氏阴性菌至关重要。我们最近发现载脂蛋白CI(ApoCI)(apoCI(1-57))能与内毒素结合，涉及一个内毒素结合基序(apoCI(48-54))，从而增强内毒素诱导的炎症反应。我们目前的目标是进一步阐明apoCI的结构和功能与其调节内毒素的特性的关系，并揭示apoCI增强内毒素生物活性的机制。我们设计并生成了N-端和C-端apoCI衍生的多肽，其中包含不同数量的交替的阳离子/疏水基序。ApoCI(1-38)、apoCI(1-30)和apoCI(35-57)能与内毒素结合，而apoCI(1-23)和apoCI(46-57)不能与内毒素结合。根据apoCI(1-38)、apoCI(1-30)和apoCI(35-57)的结合特性，apoCI(1-38)、apoCI(1-30)和apoCI(35-57)通过减少I-125-LPS与肝脏的结合而延长其血清滞留时间。因此，载脂蛋白CI(1-30)和载脂蛋白CI(35-57)在体外(RAW 264.7巨噬细胞)和体内(C57BL/6小鼠)均能增强脂多糖诱导的肿瘤坏死因子α反应。更多的体外研究表明，apoCI对内毒素反应的刺激作用类似于内毒素结合蛋白(LBP)，并依赖于CD14/Toll样受体4信号转导。(JLR)我们得出结论，apoCI的N端和C端螺旋上都含有结构元件，以结合内毒素，并通过类似于LBP的机制增强对内毒素的促炎反应。载脂蛋白CI通过其N-末端和C-末端螺旋上的内毒素结合元件，通过CD14/TLR4途径增强对内毒素的生物应答。J.Lipid Res.2010年。51：1943-1952
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