Macrophage-Elicited Osteoclastogenesis in Response to Bacterial Stimulation Requires Toll-Like Receptor 2-Dependent Tumor Necrosis Factor-Alpha Production

Ukai, Takashi; Yumoto, Hiromichi; Gibson, Frank C.; Genco, Caroline Attardo

doi:10.1128/iai.01241-07

Cited by 62 publications

(84 citation statements)

References 42 publications

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“…Although many virulence factors of P. gingivalis have been proposed to contribute to periodontal bone and tissue destruction (16,17,50), we have reported that various complex lipids of P. gingivalis are readily detected in periodontal disease sites without concurrent bacterial invasion or LPS recovery (21,51). We have now determined that specific lipid classes that are relatively minor constituents of this organism are responsible for activation of TLR2 and that dihydroceramide lipids are not responsible for these TLR2-mediated biological responses.…”

Section: Discussionmentioning

confidence: 88%

“…These studies reported engagement of TLR2 only in vitro in mouse cells. Recent reports have demonstrated TLR2-dependent periodontal bone loss in mice following oral infection with P. gingivalis (15,16). Most recently, cell adhesion mediated through the expression of fimbriae by P. gingivalis has been implicated in promoting of TLR2-dependent oral bone loss (17).…”

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confidence: 99%

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Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

et al. 2013

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eThe total cellular lipids of Porphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids of P. gingivalis and define which lipid classes account for the TLR2 engagement, based on both in vitro human cell assays and in vivo studies in mice. Specific serine-containing lipids of P. gingivalis, called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods. T oll-like receptors (TLRs) represent a diverse family of molecules that play a critical role in activating the innate immune system in response to pathogens (1, 2). Toll-like receptor 2 (TLR2) recognizes diverse molecular structures of microbial cell wall origin, including lipoteichoic acid, lipoproteins, peptidoglycan from Gram-positive bacteria, lipoarabinomannan from mycobacteria, and zymosan from yeast cell walls. TLR2 is reported to be activated by many other microbial products, including phenol-soluble modulins (3) and Porphyromonas gingivalis lipoprotein (4), lipopolysaccharide (LPS) (5-7), and fimbriae (8-10). However, two recent reports have questioned the extent to which lipoprotein, LPS, or fimbriae mediate TLR2 engagement by P. gingivalis (11,12).We previously reported that the total lipid extract of P. gingivalis promotes activation of mouse dendritic cells and inhibits osteoblast-mediated bone deposition through engagement of TLR2 (13,14). These effects were attributed to the dominant phosphorylated dihydroceramide lipids of P. gingivalis, in particular, phosphoethanolamine dihydroceramides. These studies reported engagement of TLR2 only in vitro in mouse cells. Recent reports have demonstrated TLR2-dependent periodontal bone loss in mice following oral infection with P. gingivalis (15,16). Most recently, cell adhesion mediated through the expression of fimbriae by P. gingivalis has been implicated in promoting of TLR2-dependent oral bone loss (17). In contrast, two recent reports indicated that the capacity of fimbriae to engage TLR2 is dependent on the presence of a contaminating factor that is susceptible to hydrolysis by lipoprotein lipase (11,18).In addition to effects on mouse cells, the phosphorylated dihydroceramide lipids of P. gingivalis have been shown to promote proinflammatory responses in human fibroblasts and to cause disruption of human fibroblast adherence/vitality in culture (19). However, it is not clear whether these effects require engagement of TLR2. Since the total lipid extract of P. gingivalis has been shown to activate TLR2 in mice and in mouse cells, the primary purpose of this investigation was to further identify and characterize the specific lipid classes of P. gingivalis that are responsible for engagement of TLR2 and, specifica...

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

et al. 2013

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“…P. gingivalis is a common oral bacterium that has been extensively characterized for its ability to promote gingival tissue and alveolar bone destruction. P. gingivalis LPS has been reported to use either TLR4 or TLR2 in its signaling, 19,[23][24][25] and Shapira et al reported that injecting whole killed P. gingivalis bacteria into subcutaneous chambers in SJL mice resulted in enhancement of EAE. 26 In contrast to these studies that used whole bacteria or P. gingivalis LPS, our studies focused on uniquely structured, non-LPS lipids produced by P. gingivalis.…”

Section: Discussionmentioning

confidence: 99%

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Nichols

Housley

O'Conor

et al. 2009

The American Journal of Pathology

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Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they may play a role in human inflammatory disease. To investigate whether these lipids have functional effects on autoimmunity, we administered phosphorylated dihydroceramides to mice with the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). We find that these lipids, and particularly the phosphoethanolamine dihydroceramide (PE DHC) fraction, significantly enhanced EAE. Mechanistically, PE DHC enhances EAE in mice lacking natural killer T cells, fails to enhance EAE in Toll-like receptor 2 (TLR2)-deficient mice and, in vitro, induces dendritic cell interleukin-6 secretion in a TLR2-dependent manner.

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“…TLR2 is responsible for the predominantly Th2-oriented immune response observed in progressive periodontitis (4). TLR2 was associated with exacerbation of P. gingivalisinduced periodontal bone loss due to TLR2-induced TNF-α-dependent osteoclastogenesis (12).…”

Section: Discussionmentioning

confidence: 99%

Escin inhibits lipopolysaccharide-induced inflammation in human periodontal ligament cells

Liu

Wang

Qiu

et al. 2012

Molecular Medicine Reports

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Abstract. Periodontitis is a chronic inflammatory disease associated with gram-negative subgingival microflora infection. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and anti-edematous effects. This study was designed to investigate the in vitro effects of escin on the inflammatory reaction of human periodontal ligament cells (hPDLs). hPDLs were stimulated with lipopolysaccharide (LPS). The cells were treated with various concentrations of escin. The viability of hPDLs was evaluated using the MTT method. The expression of Toll-like receptor 2 (TLR2) in hPDLs and the levels of IL-1β, TNF-α and IL-6 in the supernatant were measured. Escin significantly attenuated LPS-induced cytotoxicity in a concentration-dependent manner in hPDLs. Treatment with escin partly blocked the expression of TLR2. Escin also lowered the increase of proinflammatory cytokines (IL-1β, TNF-α and IL-6) induced by LPS. The present findings show that escin exerts a protective effect against LPS-induced inflammation in hPDLs. It was also shown that escin is a promising medicine for the treatment of periodontitis.

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Macrophage-Elicited Osteoclastogenesis in Response to Bacterial Stimulation Requires Toll-Like Receptor 2-Dependent Tumor Necrosis Factor-Alpha Production

Cited by 62 publications

References 42 publications

Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Escin inhibits lipopolysaccharide-induced inflammation in human periodontal ligament cells

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