Tetra- and penta-acylated lipid A structures of Porphyromonas gingivalis LPS differentially activate TLR4-mediated NF-κB signal transduction cascade and immuno-inflammatory response in human gingival fibroblasts.
Tetra- and penta-acylated lipid A structures of Porphyromonas gingivalis LPS differentially activate TLR4-mediated NF-κB signal transduction cascade and immuno-inflammatory response in human gingival fibroblasts.
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DOI：
10.1371/journal.pone.0058496
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jin L
中科院分区：
文献类型：
--
作者：
Herath TD;Darveau RP;Seneviratne CJ;Wang CY;Wang Y;Jin L
牙龈卟啉单胞菌是影响全世界大多数成年人的牙周病的主要病原体。越来越多的证据表明，牙周病会导致全身炎症水平升高，从而与糖尿病和心血管疾病等各种全身性疾病有关。脂多糖 (LPS) 作为牙龈卟啉单胞菌的关键毒力属性，具有大量脂质 A 异质性，包含四酰化 (LPS1435/1449) 和五酰化 (LPS1690) 结构。迄今为止，由于对LPS-宿主细胞相互作用中涉及的特定受体和信号通路的了解有限，牙龈卟啉单胞菌LPS参与牙周发病机制的确切分子机制仍不清楚。本研究系统研究了牙龈卟啉单胞菌LPS1435/1449和LPS1690对人牙龈成纤维细胞（HGF）中TLR2和TLR4信号转导表达以及促炎细胞因子IL-6和IL-8激活的影响。我们发现 LPS1435/1449 和 LPS1690 差异调节 TLR2 和 TLR4 表达。 NF-κB 通路被 LPS1690 显着激活，但不被 LPS1435/1449 激活。此外，LPS1690 诱导 NF-κB 和 p38 MPAK 通路相关基因的显着表达，例如 NFKBIA、NFKB1、IKBKB、MAP2K4 和 MAPK8。值得注意的是，LPS1690 显着上调促炎基因，包括 GM-CSF、CXCL10、G-CSF、IL-6、IL-8 和 CCL2，而 LPS1435/1449 则显着下调。阻断实验证实，TLR4 介导的 NF-κB 信号传导对于 LPS1690 诱导的 HGF 中 IL-6 和 IL-8 的表达至关重要。本研究表明牙龈卟啉单胞菌LPS的四酰化和五酰化脂质A结构差异性地激活TLR4介导的NF-κB信号通路，并显着调节HGF中IL-6和IL-8的表达。改变 LPS 脂质 A 结构的能力可能是牙龈卟啉单胞菌逃避牙龈组织先天宿主防御的策略之一，从而促进牙周发病机制。
Porphyromonas gingivalis is a major pathogen of periodontal disease that affects a majority of adults worldwide. Increasing evidence shows that periodontal disease is linked to various systemic diseases like diabetes and cardiovascular disease, by contributing to increased systemic levels of inflammation. Lipopolysaccharides (LPS), as a key virulent attribute of P. gingivalis, possesses significant amount of lipid A heterogeneity containing tetra- (LPS1435/1449) and penta-acylated (LPS1690) structures. Hitherto, the exact molecular mechanism of P. gingivalis LPS involved in periodontal pathogenesis remains unclear, due to limited understanding of the specific receptors and signaling pathways involved in LPS-host cell interactions. This study systematically investigated the effects of P. gingivalis LPS1435/1449 and LPS1690 on the expression of TLR2 and TLR4 signal transduction and the activation of pro-inflammatory cytokines IL-6 and IL-8 in human gingival fibroblasts (HGFs). We found that LPS1435/1449 and LPS1690 differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS1690 but not by LPS1435/1449. In addition, LPS1690 induced significant expression of NF-κB and p38 MPAK pathways-related genes, such as NFKBIA, NFKB1, IKBKB, MAP2K4 and MAPK8. Notably, the pro-inflammatory genes including GM-CSF, CXCL10, G-CSF, IL-6, IL-8 and CCL2 were significantly upregulated by LPS1690 while down-regulated by LPS1435/1449. Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS1690-induced expression of IL-6 and IL-8 in HGFs. The present study suggests that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS differentially activate TLR4-mediated NF-κB signaling pathway, and significantly modulate the expression of IL-6 and IL-8 in HGFs. The ability to alter the lipid A structure of LPS could be one of the strategies carried-out by P. gingivalis to evade innate host defense in gingival tissues, thereby contributing to periodontal pathogenesis.
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影响因子：
4.4
作者：
Burns, Elia;Eliyahu, Tal;Nussbaum, Gabriel
通讯作者：
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影响因子：
3.4
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