| Research Abstract |
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.
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