Innate immune system in oral mucosa, with special reference to inhibition of inflammatory and immune responses and up-regulation of antibacterial functions

在先天免疫系统中，宿主细胞中的模式识别分子（PRMs）如toll样受体（TLRs）和NOD1/2可以识别微生物的常见和特殊结构病原相关分子模式（pathogen-associated molecular patterns, PAMPs）。我们检查了口腔和相关粘膜的先天免疫系统，得到了以下发现。1)口腔及各种上皮细胞（共16个上皮细胞）在细胞表面表达TLR2和4，在细胞内表达TLR3、7、NOD1和NOD2。上皮细胞在各自合成配体的刺激下一般不分泌炎症因子，而细胞积极产生抗菌因子，如肽聚糖识别蛋白（PGRP-L, Iα, Iβ， S）和β-防御素2。这些发现表明，与正常菌群中各种微生物相互作用的上皮细胞受到负向控制，以防止过度炎症和免疫反应的诱导，同时它们积极产生抗微生物因子。2) TLR和NOD1/2配体联合刺激可协同诱导口腔上皮细胞抗微生物因子。3)据报道，最小的NOD1配体是iE-DAP [γ-D-glutamy1-meso-diaminopimelic acid (γ- d - gluu -meso- dap)]。我们证明了中位- dap和中位-硫代氨酸本身通过NOD1激活了各种人上皮细胞。当对耐药细胞进行渗透性处理时，meso-DAP明显激活了细胞，这表明meso-DAP足以激活NOD1，而nod -配体进入细胞需要D-Glu部分。4)另一方面，从正常菌群中分离出来的人牙龈成纤维细胞表达TLR1-9和NOD1/2，并在各自合成配体的刺激下积极产生炎症细胞因子。

In the innate immune system, common and peculiar structures of microbes, pathogen-associated molecular patterns (PAMPs), are recognized by pattern-recognition molecules (PRMs) such as Toll-like receptors (TLRs) and NOD1/2 in host cells. We examined the innate immune system in the oral and related mucosa and obtained the following findings. 1) Oral and various epithelial cells (total of 16 lining cells) expressed TLR2 and 4 on the cell-surface and TLR3, 7, NOD1 and NOD2 intracellularly. The epithelial cells in general did not secrete inflammatory cytokines upon stimulation with respective synthetic ligands, whereas the cells actively produced antimicrobial factors such as peptidoglycan recognition proteins (PGRP-L, Iα, Iβ, S) and β-defensin 2. These findings suggest that epithelial cells, which interact with various microbes in normal flora, are negatively controlled to prevent the induction of excessive inflammatory and immune responses, while they actively produce anti-microbial factors. 2) Combined stimulation with TLR and NOD1/2 ligands synergistically induced anti-microbial factors in oral epithelial cells. 3) Minimal NOD1 ligand has been reported to be iE-DAP [γ-D-glutamy1-meso-diaminopimelic acid (γ-D-Glu-meso-DAP)]. We demonstrated that meso-DAP and meso-lanthionine by themselves activated various human epithelial cells via NOD1. When the resistant cells were treated to increase their permeability, meso-DAP clearly activated the cells, suggesting that meso-DAP is sufficient to activate NOD1 and that the D-Glu portion is required for the NOD-ligand to be incorporated into cells. 4) On the other hand, human gingival fibroblasts, which are isolated from normal flora, expressed TLR1-9 and NOD1/2, and actively produce inflammatory cytokines upon stimulation with the respective synthetic ligands.