A cyanobacterial lipopolysaccharide antagonist inhibits cytokine production induced by Neisseria meningitidis in a human whole-blood model of septicemia
A cyanobacterial lipopolysaccharide antagonist inhibits cytokine production induced by Neisseria meningitidis in a human whole-blood model of septicemia
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DOI：
10.1128/iai.00110-08
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发表时间：
2008-07-01
影响因子：
3.1
通讯作者：
Christodoulides, Myron
中科院分区：
文献类型：
--
作者：
Jemmett, Kim;Macagno, Annalisa;Christodoulides, Myron
脑膜炎奈瑟菌引起的败血症的特征是血液中脑膜炎球菌脂多糖 (Nm-LPS) 和细胞因子产生水平增加。我们使用脑膜炎球菌败血症的体外人类全血模型来研究 CyP（一种源自蓝藻浮游丝菌 FP1 的选择性 Toll 样受体 4 (TLR4)-MD-2 拮抗剂）减少 LPS 介导的细胞因子产生的潜力。 CyP (>= 1 mu g/ml) 抑制促炎细胞因子肿瘤坏死因子 α、白细胞介素 1 β (IL-1 β) 和 IL-6 (>90%) 以及趋化因子 IL-8 和单核细胞趋化蛋白 1 (大约 50%) 的分泌，这些细胞因子是通过用纯 Nm-LPS 处理血液、通过分离的外膜以及感染不同的活脑膜炎球菌后诱导的血清群。对人树突状细胞和 TLR4 转染的 Jurkat 细胞的体外研究表明，CyP 竞争性抑制 Nm-LPS 与 TLR4 的相互作用以及随后的 NF-κ B 激活。这些数据表明，CyP 是脑膜炎球菌 LPS 的有效拮抗剂，可被视为治疗败血症的新辅助疗法。
Septicemia caused by Neisseria meningitidis is characterized by increasing levels of meningococcal lipopolysaccharide (Nm-LPS) and cytokine production in the blood. We have used an in vitro human whole-blood model of meningococcal septicemia to investigate the potential of CyP, a selective Toll-like receptor 4 (TLR4)-MD-2 antagonist derived from the cyanobacterium Oscillatoria planktothrix FP1, for reducing LPS-mediated cytokine production. CyP (>= 1 mu g/ml) inhibited the secretion of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), and IL-6 (by >90%) and chemokines IL-8 and monocyte chemoattractant protein 1 (by similar to 50%) induced by the treatment of blood with pure Nm-LPS, by isolated outer membranes, and after infection with live meningococci of different serogroups. In vitro studies with human dendritic cells and TLR4-transfected Jurkat cells demonstrated that CyP competitively inhibited Nm-LPS interactions with TLR4 and subsequent NF-kappa B activation. These data demonstrate that CyP is a potent antagonist of meningococcal LPS and could be considered a new adjunctive therapy for treating septicemia.