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Background    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- (LPS 1435/1449 ) and penta-acylated (LPS 1690 ) 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.    Methodology/Principal Findings  This study systematically investigated the effects of  P. gingivalis  LPS 1435/1449  and LPS 1690  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 LPS 1435/1449  and LPS 1690  differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS 1690  but not by LPS 1435/1449 . In addition, LPS 1690  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 LPS 1690  while down-regulated by LPS 1435/1449 . Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS 1690 -induced expression of IL-6 and IL-8 in HGFs.    Conclusions/Significance  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.

plos one

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