| Research Abstract |
In innate immunity, common and peculiar structures of microbes, pathogen-associated molecular patterns (PAMPs), are recognized by pattern-recognition molecules (PRMs) represented by Toll-like receptors (TLRs) in host cells. Another intracellular PRM family, NOD1 and NOD2, recognizes bacterial peptidoglycans. We examined innate immune responses through TLRs and NODs in various cells to elucidate the roles of innate immunity in the oral mucosa. In these experiments, only chemically synthesized ligands were used to rule out the influences of minor components in bacterial preparations ; bacterial lipopeptide Pam3CSSNA (TLR2 ligand), E.coli-type lipid A LA-15-PP (TLR4 ligand), bacterial CpG DNA (TLR9 ligand), MDP (NOD2 ligand) and iE-DAP (NOD1 ligand). We demonstrated that NOD1- or NOD2-agonist in combination with various TLR-agonists synergistically induced inflammatory cytokines in human monocytic THP-1 cells in culture. The same combinatory stimulation also induced Th1-lineage responses in human dendritic cells. Human oral epithelial cells also carried all of the TLR and NOD molecules examined to date. However, stimulation by the respective ligands did not induce inflammatory cytokines, but definitely induced anti-bacterial factors such as peptidoglycan recognition proteins (PGRP-L,Iα,Iβ,S) and β-defensin 2. Taking all of these findings in consideration, we postulate a working hypothesis : Oral epithelial cells, which interact with various bacteria in normal flora, actively produce anti-bacterial factors. The cells, however, are negatively controlled to prevent the induction of immune and inflammatory responses. When the negative regulation is turned off, excessive inflammatory responses occur, which in turn initiate tissue destruction. Once the mucosal barrier was broken, accumulated macrophages and dendritic cells initiate Th1-lineage acquired immune responses, which are were typical of oral mucosal disease represented by periodontal diseases.
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