Biological properties of the native and synthetic lipid A of Porphyromonas gingivalis lipopolysaccharide
Biological properties of the native and synthetic lipid A of Porphyromonas gingivalis lipopolysaccharide
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DOI：
10.1111/j.1399-302x.2007.00392.x
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发表时间：
2008-02-01
影响因子：
--
通讯作者：
Umemoto, T.
中科院分区：
文献类型：
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作者：
Kumada, H.;Haishima, Y.;Umemoto, T.
导言和方法：化学合成了从牙龈卟啉单胞菌脂多糖（LPS）中分离的脂质A中发现的五酰基和二磷酰基脂质A分子，并对其特性进行了评价，以再次确认其有趣的生物活性，包括低内毒素和对LPS无反应的C3 H/HeJ小鼠细胞的活性。合成的牙龈卟啉单胞菌脂质A（合成的Pg-LA）在对LPS应答小鼠和细胞的所有测定中表现出几乎等同于大肠杆菌型合成脂质A（化合物506）的强活性。牙龈卟啉单胞菌的LPS和天然脂质A显示出总体内毒素活性，但与合成类似物相比，其效力降低。在使用C3 H/HeJ小鼠细胞的测定中，LPS和天然脂质A显著刺激脾细胞以引起有丝分裂，并且腹膜巨噬细胞诱导肿瘤坏死因子-α和白细胞介素-6产生。然而，合成的Pg-LA和化合物506对LPS无反应的细胞没有显示出活性。使用包括抗人Toll样受体2（TLR 2）和TLR 4/MD-2复合物单克隆抗体在内的一些抑制剂的抑制试验表明，合成的Pg-LA的生物活性仅通过TLR 4信号通路介导，TLR 4可能作为LPS的受体，而TLR 2可能与CD 14一起与LPS和牙龈卟啉单胞菌天然脂质A的信号级联相关，结论：牙龈卟啉单胞菌LPS和天然脂质A的生物学活性（包括其通过TLR 2介导的途径对C3 H/HeJ小鼠细胞的活性）的缓和和降低可能由具有多个脂质A部分的天然制剂中存在的生物活性污染物或低酰化分子介导。
Introduction and methods: A pentaacyl and diphosphoryl lipid A molecule found in the lipid A isolated from Porphyromonas gingivalis lipopolysaccharide (LPS) was chemically synthesized, and its characteristics were evaluated to reconfirm its interesting bioactivities including low endotoxicity and activity against LPS-unresponsive C3H/HeJ mouse cells.Results: The synthesized P. gingivalis lipid A (synthetic Pg-LA) exhibited strong activities almost equivalent to those of Escherichia coli-type synthetic lipid A (compound 506) in all assays on LPS-responsive mice, and cells. LPS and native lipid A of P. gingivalis displayed overall endotoxic activities, but its potency was reduced in comparison to the synthetic analogs. In the assays using C3H/HeJ mouse cells, the LPS and native lipid A significantly stimulated splenocytes to cause mitosis, and peritoneal macrophages to induce tumor necrosis factor-alpha and interleukin-6 production. However, synthetic Pg-LA and compound 506 showed no activity on the LPS-unresponsive cells. Inhibition assays using some inhibitors including anti-human Toll-like receptor 2 (TLR2) and TLR4/MD-2 complex monoclonal antibodies showed that the biological activity of synthetic Pg-LA was mediated only through the TLR4 signaling pathway, which might act as a receptor for LPS, whereas TLR2, possibly together with CD14, was associated with the signaling cascade for LPS and native lipid A of P. gingivalis, in addition to the TLR4 pathway.Conclusion: These results suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including their activity on C3H/HeJ mouse cells via the TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having multiple lipid A moieties.