Lipopolysaccharides from Periodontopathic BacteriaPorphyromonas gingivalisandCapnocytophaga ochraceaAre Antagonists for Human Toll-Like Receptor 4

Abstract

Toll-like receptors (TLRs) 2 and 4 have recently been identified as possible signal transducers for various bacterial ligands. To investigate the roles of TLRs in the recognition of periodontopathic bacteria by the innate immune system, a Chinese hamster ovary (CHO) nuclear factor-B (NF-B)-dependent reporter cell line, 7.7, which is defective in both TLR2-and TLR4-dependent signaling pathways was transfected with human CD14 and TLRs. When the transfectants were exposed to freeze-dried periodontopathic bacteria, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Capnocytophaga ochracea, and Fusobacterium nucleatum, and a non-oral bacterium, Escherichia coli, all species of the bacteria induced NF-B-dependent CD25 expression in 7.7/huTLR2 cells. Although freeze-dried A. actinomycetemcomitans, F. nucleatum, and E. coli also induced CD25 expression in 7.7/huTLR4 cells, freeze-dried P. gingivalis did not. Similarly, lipopolysaccharides (LPS) extracted from A. actinomycetemcomitans, F. nucleatum, and E. coli induced CD25 expression in 7.7/huTLR4 cells, but LPS from P. gingivalis and C. ochracea did not. Furthermore, LPS from P. gingivalis and C. ochracea attenuated CD25 expression in 7.7/huTLR4 cells induced by repurified LPS from E. coli. LPS from P. gingivalis and C. ochracea also inhibited the secretion of interleukin-6 (IL-6) from U373 cells, the secretion of IL-1␤ from human peripheral blood mononuclear cells, and ICAM-1 expression in human gingival fibroblasts induced by repurified LPS from E. coli. These findings indicated that LPS from P. gingivalis and C. ochracea worked as antagonists for human TLR4. The antagonistic activity of LPS from these periodontopathic bacteria may be associated with the etiology of periodontal diseases.

Human dendritic cells respond to Porphyromonas gingivalis LPS by promoting a Th2 effector response in vitro

“…Recent studies suggest that TLR2 might be the primary signal-transducing molecule for LPS from certain nonenterobacterial Gramnegative organisms, including P. gingivalis [9,11,12] and Leptospira interrogans [32]. However, controversy still exists in the case of P. gingivalis LPS, as it appears to also have activity for TLR4 [12,[33][34][35]. P. gingivalis LPS has been shown to antagonize the activity of TLR4 agonists [33], and several studies in fibroblasts indicate that signaling in response to P. gingivalis LPS is mediated, in part, through TLR4 [35,36].…”

Identification of Signaling Pathways in Macrophage Exposed to Porphyromonas gingivalis or to Its Purified Cell Wall Components

“…It has also been shown to antagonize Escherichia coli LPS-dependent induction of E-selectin expression, p38 MAPK activation, and NF-␣B activation in human endothelial cells and monocytes (2,3). The ability of P. gingivalis LPS to down-regulate innate immune responses to other LPS (E. coli) may play a role in allowing this oral pathogen to evade the normal surveillance system so essential in maintaining periodontal health (4). Fimbriae are reported to mediate the bacterial adherence to and invasion of epithelial cells and gingival fibroblasts (5).…”

MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to AntagonizeEscherichia coliLipopolysaccharide at the TLR4 Signaling Complex

“…For example, LPS isolates from the oral pathogen, P. gingivalis, have been shown to antagonize E. coli LPS-dependent induction of E-selectin expression, p38 MAPK activation, and NF-B activation in human endothelial cells (22)(23)(24). P. gingivalis LPS has also been shown to inhibit E. coli LPS-stimulated release of TNF-␣, IL-␤, and IL-6 in human monocytes, as well as ICAM-1 expression in human gingival fibroblasts (25,26). Recently, our laboratory performed structural analyses of antagonistic P. gingivalis LPS preparations and found that they are comprised mainly of tetra-acylated lipid A structures (27,28).…”

“…Recently, our laboratory performed structural analyses of antagonistic P. gingivalis LPS preparations and found that they are comprised mainly of tetra-acylated lipid A structures (27,28). The ability of antagonistic P. gingivalis LPS to down-regulate critical innate immune responses has been postulated to play an important role in this oral pathogen's ability to override the normal surveillance system that is essential to maintaining periodontal health (22,23,26,29). In addition, recent study has suggested that antagonist forms of LPS isolated from Helicobacter pylori play a role in the ability of this microbe to induce gastric inflammation (30).…”