Analysis of endotoxin antagonism of lipoteichoic acids from oral streptococci

1.口腔链球菌、血链球菌和变形链球菌的脂磷壁酸(LTA)可拮抗CD14阳性的人牙龈成纤维细胞(HGF)和人单核细胞对内毒素(内毒素，脂多糖)及其活性部分--合成脂A产生炎性细胞因子的作用。除了作为细菌成分受体的CD14外，Toll样受体(TLRs)还将成分的信号传导到细胞内。其他细菌和脂多糖的LTA分别通过CD14/TLR2-和CD14/TLR4依赖的途径激活小鼠巨噬细胞。作为一种已知的脂蛋白拮抗剂，合成脂A前体(LA-14-PP)抑制CD14/TLR4配体(LPS)和CD14/TLR2配体(LTA)在人体系统中的功能，提示CD14参与了这种拮抗作用。抗CD14抗体可抑制LTAS与人单核细胞的结合，天然聚丙烯酰胺凝胶电泳法显示LTAS与重组CD14结合，表明LTAS的拮抗作用是通过与细胞表面CD14.5竞争介导的。牙周致病性牙龈卟啉单胞菌半胱氨酸蛋白酶(牙痛)和人中性粒细胞丝氨酸蛋白酶(弹性酶)优先降解人单核细胞和肝细胞生长因子上的CD14，导致细胞的内毒素反应性下调。

1. Lipoteichoic acids (LTAs) of oral streptococci, Streptococcus sanguis and Streptococcus mutans, was shown to antagonize the activity of inflammatory cytokine production from CD14-positive human gingival fibroblasts (HGF) and human monocytes in response to endotoxin (LPS, lipopolysaccharide) and its active moiety, synthetic lipid A.2. In addition to CD14 as a bacterial component receptor, Toll-like receptors (TLRs) transduce signals of the components into the cells. LTAs of other bacteria and LPS activated murine macrophages in a CD14/TLR2-and CD14/TLR4-dependent pathway, respectively, using gene knockout mice.3. An well known LPS antagonist, a synthetic lipid A precursor (LA-14-PP) inhibited the function of CD14/TLR4 ligand (LPS) as well as CD14/TLR2 ligand (LTA) in human system, suggesting that CD14 is critically involved in the antagonism.4. Binding of oral streptococcal LTAs to human monocytes was inhibited by anti-CD14 antibody and the LTAs binded to recombinant CD14 in a native-polyacrylamide gel electrophoresis, showing that the antagonism of the LTAs is mediated by competing with cell surface CD14.5. Periodontal pathogenic Porphyromonas gingivalis cysteine proteinase (gingipain) and human neutrophil serine proteinase (elastase) preferentially proteolysed CD14 on human monocytes and HGF, resulting in down-modulation of LPS responsiveness of the cells.