Analysis of endotoxin antagonism of lipoteichoic acids from oral streptococci

口腔链球菌脂磷壁酸内毒素拮抗作用分析

• 批准号: 11671796
• 负责人: SUGAWARA Shunji
• 金额: $ 2.5万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671796/
• 关键词: oral streptococci; lipoteichoic acids; endotoxin; antagonist; CD14; Toll-like receptors; periodontitis

1. Lipoteichoic acids (LTAs) of oral streptococci, Streptococcus sanguis and Streptococcus mutans, was shown to antagonize the activity of inflammatory cytokine production from CD14-positive human gingival fibroblasts (HGF) and human monocytes in response to endotoxin (LPS, lipopolysaccharide) and its active moiety, synthetic lipid A.2. In addition to CD14 as a bacterial component receptor, Toll-like receptors (TLRs) transduce signals of the components into the cells. LTAs of other bacteria and LPS activated murine macrophages in a CD14/TLR2-and CD14/TLR4-dependent pathway, respectively, using gene knockout mice.3. An well known LPS antagonist, a synthetic lipid A precursor (LA-14-PP) inhibited the function of CD14/TLR4 ligand (LPS) as well as CD14/TLR2 ligand (LTA) in human system, suggesting that CD14 is critically involved in the antagonism.4. Binding of oral streptococcal LTAs to human monocytes was inhibited by anti-CD14 antibody and the LTAs binded to recombinant CD14 in a native-polyacrylamide gel electrophoresis, showing that the antagonism of the LTAs is mediated by competing with cell surface CD14.5. Periodontal pathogenic Porphyromonas gingivalis cysteine proteinase (gingipain) and human neutrophil serine proteinase (elastase) preferentially proteolysed CD14 on human monocytes and HGF, resulting in down-modulation of LPS responsiveness of the cells.

1. 口腔链球菌、血链球菌和变形链球菌的脂磷壁酸 (LTA) 被证明可以拮抗 CD14 阳性人牙龈成纤维细胞 (HGF) 和人单核细胞响应内毒素（LPS、脂多糖）及其活性部分、合成物产生炎症细胞因子的活性 脂质A.2。除了 CD14 作为细菌成分受体外，Toll 样受体 (TLR) 还将这些成分的信号转导到细胞中。使用基因敲除小鼠，其他细菌的 LTA 和 LPS 分别以 CD14/TLR2 和 CD14/TLR4 依赖性途径激活小鼠巨噬细胞。 3．一种众所周知的LPS拮抗剂，合成的脂质A前体(LA-14-PP)抑制人体系统中CD14/TLR4配体(LPS)以及CD14/TLR2配体(LTA)的功能，表明CD14在拮抗作用中发挥着重要作用。4．抗CD14抗体抑制口腔链球菌LTA与人单核细胞的结合，并且在天然聚丙烯酰胺凝胶电泳中LTA与重组CD14结合，表明LTA的拮抗作用是通过与细胞表面CD14.5竞争来介导的。牙周致病性牙龈卟啉单胞菌半胱氨酸蛋白酶（gingipain）和人中性粒细胞丝氨酸蛋白酶（弹性蛋白酶）优先水解人单核细胞和 HGF 上的 CD14，导致细胞的 LPS 反应性下调。

项目成果

Sugawara,S.: "Proteolysis of human monocyte CD14 by cysteine proteinases(gingipains)from Porphyromonas gingivalis leading to lipopolysaccharide hyporesponsiveness."The Journal of Immunology. 165. 411-418 (2000)

Sukawara,S.：“牙龈卟啉单胞菌的半胱氨酸蛋白酶（牙龈蛋白酶）对人单核细胞 CD14 进行蛋白水解，导致脂多糖反应性低下。”《免疫学杂志》。

Takeuchi, O.: "Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components."Immunity. 11-4. 443-451 (1999)

Takeuchi, O.：“TLR2 和 TLR4 在识别革兰氏阴性和革兰氏阳性细菌细胞壁成分方面的不同作用。”免疫。

Nemoto, E.: "Increase of CD26/dipeptidyl peptidase IV expression on human gingival fibroblasts upon stimulation with cytokines and bacterial components."Infect Immun.. 67-12. 6225-6233 (1999)

Nemoto, E.：“细胞因子和细菌成分刺激后人牙龈成纤维细胞上 CD26/二肽基肽酶 IV 表达增加。”感染免疫.. 67-12。

Kai,K.: "Lipopolysaccharide-dependent down-regulation of CD27 expression on T cells activated with superantigen."Immunology. 98. 289-295 (1999)

Kai,K.：“超抗原激活的 T 细胞上 CD27 表达的脂多糖依赖性下调。”免疫学。

Nemoto,E.: "Cleavage of CD14 on human gingival fibroblasts cocultured with activated neutrophils is mediated by human leukocyte elastase resulting in down-regulation of lipopolysaccharide-induced IL-8 production."The Journal of Immunology. 165. 5807-5813

Nemoto,E.：“与活化的中性粒细胞共培养的人牙龈成纤维细胞上 CD14 的裂解是由人白细胞弹性蛋白酶介导的，导致脂多糖诱导的 IL-8 产生下调。”《免疫学杂志》。