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

Toll样受体(TLR)参与宿主天然免疫系统识别微生物模式的能力。我们研究了宿主天然免疫系统对各种细菌成分的识别，特别是牙周组织中的细胞，与口腔粘膜疾病的发病机制有关。我们从牙周病牙龈卟啉单胞菌中分离出三种半胱氨酸蛋白酶(L)，它们能裂解人单核细胞表面的C14膜(MCD14)，导致细胞对脂多糖的低反应性。(2)人白细胞弹性蛋白酶对人牙龈成纤维细胞(HGF)表面的mCD14进行切割，导致HGF细胞的低反应性。(3)与结肠上皮细胞相反，缺乏mCD14的牙龈上皮细胞即使在可溶性CD14(SCD14)存在的情况下，也不能对内毒素、肽聚糖(PGN)、PGN的关键成分胞壁二肽(MDP)或革兰氏阳性菌产生的脂磷壁酸(LTA)产生反应。(4)由表皮葡萄球菌制备的水溶性PGN，SEPS以TLR2依赖的方式激活细胞。当SEPs的糖链被酶切割时，SEPs的TLR2依赖活性消失，MDP在这方面也没有活性。(5)MDP以CD14和TLR2不依赖的方式激活人单核细胞，并上调MyD88的表达，导致MDP与依赖TLR4的激活剂LPS或LTA协同激活单核细胞。(6)干扰素-γ通过上调mCD14和MyD88mRNA的表达，增强肝细胞生长因子对内毒素的反应性。我们的实验室正在进行进一步的研究，以确定细菌成分和宿主天然免疫系统之间的相互作用与牙周病的发病机制。

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.