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Bacterial cell surface amphiphiles and periodontal diseases - Study on the role of CD14 molecule in periodontal tissues -

细菌细胞表面两亲物与牙周疾病-CD14分子在牙周组织中的作用研究-

基本信息

批准号：
10470378
负责人：
TAKADA Haruhiko
金额：
$ 8.19万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Bacterial cell surface amphiphiles exhibit various biological activities. Endotoxic lipopolysaccharides (LPS) distributed in the outer membrane of gram-negative bacteria and lipoteichoic acid (LTA) distributed in the cell surfaces of gram-positive bacteria are representative bioactive amphiphiles. Bacterial amphiphiles activate host cells such as macrophages through membrane CD14 (mCD14) expressed on cell surfaces. Last year, we demonstrated the presence of two types of human gingival fibroblasts that highly and lowly express mCD14, and the former cells produced interleukin-8 (IL-8) upon stimulation with LPS and lipid A from Enterobacteriaceae. This year, we found that 1. Bacillus subtilis LTA also activated human gingival fibroblasts via mCD14, whereas LTA from oral streptococci such as Streptococcus sanguis and Streptococcus mutans acted as an LPS-antagonist to inhibit IL-8-induction by LPS. 2. The LPS fraction from Prevotella intermedia, periodontal disease-associated bacteria, activated human dental pulp cells that lack mCD14, in a soluble CD14- and nuclear factor AP-1-dependent manner. 3. Furthermore, in collaboration with Prof. Shizuo Akira, Osaka University, we studied the relationship between amphiphiles and the Toll-like receptor (TLR) system, which was recently revealed to be associated with CD14 and is involved in LPS signaling. We revealed that LTA as well as LPS was recognized by TLR4 in contrast to previous reports. We also obtained evidence suggesting that a bioactive glycoprotein, PGP, prepared from P. intermedia, was recognized by TLR2.With the viewpoint that "bacterial products overstimulate the innate immune system, and result in tissue destruction," we would like to reveal how the CD14/TLR system recognizes and responds to microbes in periodontal tissues in relation to the pathogenesis of periodontal diseases.

细菌细胞表面两亲物表现出多种生物活性。分布在革兰氏阴性菌外膜的内毒素脂多糖（LPS）和分布在革兰氏阳性菌细胞表面的脂磷壁酸（LTA）是具有代表性的生物活性两亲物。细菌两亲物通过细胞表面表达的膜 CD14 (mCD14) 激活巨噬细胞等宿主细胞。去年，我们证明存在两种高表达和低表达 mCD14 的人类牙龈成纤维细胞，前一种细胞在受到来自肠杆菌科细菌的 LPS 和脂质 A 刺激后产生白细胞介素 8 (IL-8)。今年，我们发现 1. 枯草芽孢杆菌 LTA 也通过 mCD14 激活人类牙龈成纤维细胞，而来自口腔链球菌（如血链球菌和变形链球菌）的 LTA 可以作为 LPS 拮抗剂，抑制 LPS 诱导的 IL-8。 2. 来自中间普雷沃菌（牙周病相关细菌）的 LPS 级分，以可溶性 CD14 和核因子 AP-1 依赖性方式激活缺乏 mCD14 的人牙髓细胞。 3. 此外，我们与大阪大学 Shizuo Akira 教授合作，研究了两亲物与 Toll 样受体 (TLR) 系统之间的关系，最近发现该系统与 CD14 相关并参与 LPS 信号转导。我们透露，与之前的报道相比，LTA 和 LPS 都被 TLR4 识别。我们还获得了证据表明，从 P. intermedia 中制备的生物活性糖蛋白 PGP 可以被 TLR2 识别。本着“细菌产物过度刺激先天免疫系统，导致组织破坏”的观点，我们希望揭示 CD14/TLR 系统如何识别和响应牙周组织中的微生物，从而与牙周病的发病机制相关。