Department of Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.
Innate Immun. 2011 Dec;17(6):517-25. doi: 10.1177/1753425910383999. Epub 2010 Nov 18.
Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria and important in the induction of pro-inflammatory responses. Recently, novel LPS species derived from Neisseria meningitidis H44/76 by insertional inactivation of the lpxL1 and lpxL2 genes have been created with a lipid A portion consisting of five (penta-acylated lpxL1) or four (tetra-acylated lpxL2) fatty acids connected to the glucosamine backbone instead of six fatty acids in the wild-type LPS. We show that these mutant LPS-types are poor inducers of cytokines (tumor-necrosis factor-α, IL-1β, IL-10, IL-RA) in human mononuclear cells. Both penta- and tetra-acylated meningococcal LPSs were able to inhibit cytokine production by wild-type Escherichia coli or meningococcal LPS. Binding of FITC-labelled E. coli LPS TLR4 transfected Chinese hamster ovary (CHO) cells was inhibited by both mutant LPS-types. Experiments with CHO fibroblasts transfected with human CD14 and TLR4 showed that the antagonizing effect was dependent on the expression of human TLR4. In contrast to the situation in humans, lpxL1 LPS has agonistic activity for cytokine production in peritoneal macrophages of DBA mice, and exacerbated arthritis in murine collagen induced arthritis model. N. meningitidis lipid A mutant LPSs lpxL1 and lpxL2 function as LPS antagonists in humans by inhibiting TLR4-dependent cytokine production but have agonistic activity in mice.
脂多糖是革兰氏阴性菌外膜的主要成分，在诱导促炎反应中起重要作用。最近，通过插入失活 lpxL1 和 lpxL2 基因，从脑膜炎奈瑟菌 H44/76 中产生了新型 LPS 种类，其脂质 A 部分由连接到葡糖胺骨架上的五个（五酰化 lpxL1）或四个（四酰化 lpxL2）脂肪酸组成，而不是野生型 LPS 中的六个脂肪酸。我们表明，这些突变型 LPS 类型在人单核细胞中是细胞因子（肿瘤坏死因子-α、IL-1β、IL-10、IL-RA）的弱诱导剂。五酰化和四酰化脑膜炎奈瑟氏菌 LPS 都能够抑制野生型大肠杆菌或脑膜炎奈瑟氏菌 LPS 的细胞因子产生。FITC 标记的大肠杆菌 LPS TLR4 转染中国仓鼠卵巢（CHO）细胞的结合被两种突变型 LPS 抑制。用转染人 CD14 和 TLR4 的 CHO 成纤维细胞进行的实验表明，拮抗作用依赖于人 TLR4 的表达。与人类情况相反，lpxL1 LPS 在 DBA 小鼠的腹腔巨噬细胞中具有细胞因子产生的激动活性，并在鼠胶原诱导性关节炎模型中加重关节炎。脑膜炎奈瑟菌脂多糖突变体 LPS lpxL1 和 lpxL2 通过抑制 TLR4 依赖性细胞因子产生在人类中作为 LPS 拮抗剂起作用，但在小鼠中具有激动活性。
