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Recognition of Cell-Surface Components of Bacteria in Innate Immune System, with Special Reference to the Role of Toll-Like Receptors

先天免疫系统中细菌细胞表面成分的识别，特别是 Toll 样受体的作用

基本信息

批准号：
12470380
负责人：
TAKADA Haruhiko
金额：
$ 9.15万
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：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Toll-like receptors (TLR) are involved in the ability of the host innate immune system to recognize microbial patterns. We studied recognition of various bacterial components by the host innate immune system, especially cells in periodontal tissues, in relation to the pathogenesis of mucosal diseases in the oral cavity. We obtained the following findings, (l) Three cysteine proteases, gingipains, from periodontopathic Porphyromonas gingivalis cleaved membrane C 14 (mCD14) on human monocytes, leading to lipopolysaccharide (LPS) hyporesponsiveness of the cells. (2) Human leukocyte elastase cleaved mCD14 on human gingival fibroblasts (HGF), resulting in LPS hyporesponsiveness of the cells. (3) Gingival epithelial cells that lacked mCD14 did not respond to LPS, peptidoglycan (PGN), muramyldipeptide (MDP) which is a critical moiety of PGN, or lipoteichoic acids (LTA) from gram-positive bacteria even in the presence of soluble CD14 (sCD14) in contrast to the response of colonic epithelial cells. (4) Water-soluble PGN, SEPS, prepared from Staphylococcus epidermidis activated cells in a TLR2-dependent manner. When the glycan chain of SEPS was cleaved enzymatically, the TLR2-dependent activity of SEPS disappeared, and MDP was also inactive in this respect. (5) MDP activated human monocytic cells in a CD14- and TLR2-independent manner and up-regulated expression of MyD88, resulting in synergistic activation of the cells in combination with LPS or LTA, both of which are TLR4-dependent activators. (6) Interferon-γ primed HGF to increase response to LPS through up-regulation of mCD14 and MyD88 mRNA expression. Further studies are in progress in our laboratory to identify interactions between bacterial components and the host innate immune system in relation to pathogenesis of periodontal diseases.

Toll样受体（TLR）参与宿主先天免疫系统识别微生物模式的能力。我们研究了宿主先天免疫系统，特别是牙周组织中的细胞对各种细菌成分的识别，这些细菌成分与口腔粘膜疾病的发病机制有关。结果表明：（1）牙周病牙龈卟啉单胞菌（Porphyromonas gingivalis）的三种半胱氨酸蛋白酶（gingipains）能裂解人单核细胞膜C14（mCD 14），导致单核细胞对脂多糖（LPS）的低反应性。(2)人白细胞弹性蛋白酶切割人牙龈成纤维细胞（HGF）上的mCD 14，导致细胞的LPS低反应性。(3)缺乏mCD 14的牙龈上皮细胞对LPS、肽聚糖（PGN）、胞壁酰二肽（MDP）（PGN的关键部分）或来自革兰氏阳性菌的脂磷壁酸（LTA）没有反应，即使在可溶性CD 14（sCD 14）存在下也是如此，这与结肠上皮细胞的反应相反。(4)水溶性PGN，SEPS，以TLR 2依赖性方式由表皮葡萄球菌激活细胞制备。当SEPS的聚糖链被酶切时，SEPS的TLR 2依赖性活性消失，MDP在这方面也无活性。(5)MDP以CD 14和TLR 2非依赖性方式激活人单核细胞，并上调MyD 88的表达，导致细胞与LPS或LTA（两者均为TLR 4依赖性激活剂）组合的协同激活。(6)IFN-γ通过上调mCD 14和MyD 88 mRNA的表达，促进HGF对LPS的应答。我们实验室正在进行进一步的研究，以确定细菌成分和宿主先天免疫系统之间的相互作用与牙周病的发病机制。