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

细菌细胞表面的两亲分子具有多种生物活性。分布于革兰氏阴性菌外膜的内毒素脂多糖(LPS)和分布于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分子。细菌两亲性通过表达在细胞表面的CD14(MCD14)膜激活宿主细胞，如巨噬细胞。去年，我们证实了两种类型的人牙龈成纤维细胞的存在，它们高表达和低表达mCD14，前者在内毒素和肠杆菌科脂质A刺激下产生白介素8(IL-8)。本研究发现：1.枯草芽孢杆菌LTA也可通过mCD14激活人牙龈成纤维细胞，而口腔链球菌如血链球菌和变形链球菌的LTA则作为内毒素拮抗剂，抑制内毒素诱导的IL-8的产生。2.牙周病相关细菌中间普氏杆菌的脂多糖以可溶性CD14和核因子AP-1依赖的方式激活缺乏mCD14的人牙髓细胞。3.此外，我们与大阪大学的秋井静三教授合作，研究了两亲分子与Toll样受体(TLR)系统之间的关系，TLR系统最近被发现与CD14相关，并参与了内毒素信号转导。与以前的报道不同，我们发现TLR4识别LTA和内毒素。我们还获得了证据表明，从中间P.media中提取的一种生物活性糖蛋白Pgp被TLR2识别。本着细菌产物过度刺激天然免疫系统，导致组织破坏的观点，我们想要揭示CD14/TLR系统如何识别和响应牙周组织中的微生物，从而与牙周疾病的发病有关。

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.