UMLS:C0031099 - FACTA Search

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Query: UMLS:C0031099 (periodontitis)
12,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the inflammatory gingival tissues of patients with periodontitis, cytokines such as interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha have been detected. Gingival fibroblasts are the major constituents of gingival tissue. We recently demonstrated that lipopolysaccharide (LPS) from periodontopathic bacteria induces inflammatory reactions in various tissues via CD14 and/or Toll-like receptors (TLRs) in gingival tissues [Biochem. Biophys. Res. Commun. 273 (2000) 1161]. To confirm this, we examined the expression of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, CD14, TLR2, and TLR4 in human gingival fibroblasts (HGFs) obtained from patients with healthy or inflammatory gingiva using DNA microarray analysis. We also studied the expression levels of these proteins by flow cytometric analysis (FACS). The expression levels of all eight genes in the HGFs of the Inflammatory group were significantly higher than those in the Healthy group on DNA microarray analysis. FACS revealed that the expression levels of all eight proteins on the HGFs of the Inflammatory group were higher than those on the Healthy group. Our data indicated that these eight proteins in HGFs are involved in inflammatory conditions in the gingiva, including periodontal disease. Our results suggested that these eight proteins, in turn, act directly or indirectly on the immune response by activating host cells involved in inflammatory processes.
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PMID:DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. 1276 25

Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) of the innate immune system form functional receptor complexes that recognize and respond to pathogen-associated molecular patterns (PAMPs). Porphyromonas gingivalis is an important pathogen in human periodontitis and has also been implicated in atherosclerosis. A major virulence factor of this pathogen is the fimbriae, which function as a surface adhesin. Here we present evidence that fimbriae also constitute a predominant P. gingivalis proinflammatory molecule which activates the TLR signaling pathway resulting in induction of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and chemokines (IL-8) in monocytic cells. Although TLR2 and TLR4 mediate cellular activation in response to fimbriae, other PRRs, namely CD14 and CD11b/CD18, are involved in the recognition of fimbriae. We thus propose that fimbriae function as a PAMP which interacts with a PRR multi-receptor complex, where CD14 and CD11b/CD18 function as recruiting receptors and TLRs function as signaling receptors. In addition to cytokine induction, TLR activation by fimbriae also results in upregulation of the CD40, CD80, and CD86 costimulatory molecules in antigen-presenting cells, suggesting that fimbriae are sensed as a potential "danger" to the host immune system. Moreover, proinflammatory cytokine induction is attenuated upon repeated cellular stimulation with P. gingivalis fimbriae. This mechanism of tolerance induction which serves to mitigate excessive and potentially harmful inflammatory reactions appears to be due partly to fimbria-induced downregulation of the expression of interleukin-1 receptor-associated kinase-1 (IRAK-1), an important signaling intermediate of the TLR pathway. Understanding the molecular basis of how the host recognizes and responds to P. gingivalis fimbriae is essential for developing molecular approaches to control P. gingivalis-induced inflammatory responses in periodontal disease and perhaps atherosclerosis.
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PMID:Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors. 1519 95

Human immunoglobulin G2 (IgG2) responses are gamma interferon (IFN-gamma) dependent, and monocyte-derived dendritic cells (mDCs) promote IgG2 production. DCs spontaneously emerge from monocytes in cultures prepared from localized aggressive periodontitis (LagP) patients, and these patients have high levels of IgG2 that is reactive with Actinobacillus actinomycetemcomitans. These results prompted the hypothesis that an interaction between mDCs and A. actinomycetemcomitans promotes IFN-gamma production, and IFN-gamma is known to promote both immunopathology and protective IgG2. A. actinomycetemcomitans induced mDCs to produce interleukin-12 (IL-12), and the addition of A. actinomycetemcomitans and DCs to cultured peripheral blood lymphocytes elicited high levels of IFN-gamma within just 24 h. In contrast, IL-4 was not detectable although DC-derived IL-10 production was apparent. A. actinomycetemcomitans-stimulated macrophages prepared from the same monocytes lacked the ability to induce IL-12 or IFN-gamma responses. NK cells of the innate immune system were the primary source of this early IFN-gamma, although CD8 T cells also contributed some. The NK cell-derived IFN-gamma was IL-12 dependent, and A. actinomycetemcomitans-DC interactions were Toll-like receptor 4 dependent. A. actinomycetemcomitans and A. actinomycetemcomitans lipopolysaccharide (LPS) were more potent than Escherichia coli and E. coli LPS in the ability to induce DC IL-12 and IFN-gamma. The ability of A. actinomycetemcomitans-stimulated DCs to induce NK cells to rapidly produce IFN-gamma in the absence of detectable IL-4 suggests their potential for skewing responses toward Th1. This may help explain the presence of Th1-associated cytokines in gingival crevicular fluid (GCF) from LagP patients and the high levels of IgG2 in their serum and GCF that is reactive with A. actinomycetemcomitans.
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PMID:Dendritic cells stimulated with Actinobacillus actinomycetemcomitans elicit rapid gamma interferon responses by natural killer cells. 1532 2

The inflammatory response to chronic infections such as periodontitis may be central to the systemic implications of these diseases. This study examined the possible association between specific gene polymorphisms and the systemic inflammatory response in individuals suffering from severe generalized periodontitis. Ninety-four subjects with periodontitis were genotyped for polymorphisms in IL-1A (-889), IL-1B (-511, +3954), TNF-A (-308), IL-6 (-174) and TLR4 (-299, -399) genes. We found that the genotypes for IL-1A or IL-6 are associated with higher levels of serum IL-6 (P < 0.03) and serum CRP (P < 0.05), similarly the TNF-A genotype is associated with higher levels of serum IL-6 (P < 0.05) after correction for age, body mass index, gender, ethnicity and cigarette smoking. Systemic inflammatory responses are higher in severe periodontitis patients carrying rare alleles for functional inflammatory gene polymorphisms. These results suggest that cytokine genotypes are important determinants of the systemic inflammatory response in subjects with periodontitis. Genetic polymorphism therefore, may in part explain the reported association between periodontitis and systemic disease.
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PMID:Gene polymorphisms in pro-inflammatory cytokines are associated with systemic inflammation in patients with severe periodontal infections. 1534 23

Epithelial tissues provide both a physical barrier and an antimicrobial barrier. Antimicrobial peptides of the human beta-defensin (hBD) family are part of the innate immune responses that play a role in mucosal defense. hBDs are made in epithelia including oral epithelium where the bacterial load is particularly great. hBD-2 and hBD-3 are up-regulated in response to bacterial stimuli. Previous studies show that hBD-2 expression in human gingival epithelial cells (GEC) is stimulated by both nonpathogenic and pathogenic bacteria, including Porphyromonas gingivalis, a Gram-negative pathogen associated with periodontitis. Present evidence suggests that hBD-2 expression in GEC uses several signaling pathways, including an NF-kappaB-mediated pathway but without apparent LPS-TLR4 signaling. Protease-activated receptors (PAR) are G-protein-coupled receptors that mediate cellular responses to extracellular proteinases. P. gingivalis secretes multiple proteases that contribute to its virulence mechanisms. To determine whether PAR signaling is used in hBD-2 induction, GEC were stimulated with wild-type P. gingivalis or mutants lacking one or more proteases. hBD-2 mRNA expression was reduced in GEC stimulated with single protease mutants (11-67% compared with wild type), strongly reduced in double mutants (0.1-16%), and restored to wild-type levels (93%) in mutant with restored protease activity. Stimulation by wild type was partially blocked by inhibitors of phospholipase C, a main signaling pathway for PARs. Expression of hBD-3 was unaffected. Peptide agonist of PAR-2, but not PAR-1 activator, also induced hBD-2 in GEC. Thus, P. gingivalis proteases are directly involved in regulation of hBD-2 in cultured GEC, and this induction partially uses the PAR-2 receptor and signaling pathway.
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PMID:Protease-activated receptor signaling increases epithelial antimicrobial peptide expression. 1547 61

The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2(+) and TLR4(+) cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2(+) but not TLR4(+) cells increase linearly with inflammation (r(2) = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mphi) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1beta (IL-1beta) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1beta mRNA is induced and tumor necrosis factor alpha (TNF-alpha), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1beta mRNA and induces a ca. 10-fold reduction in TNF-alpha secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-alpha were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.
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PMID:Oral mucosal endotoxin tolerance induction in chronic periodontitis. 1566 6

Periodontitis is an inflammatory disease affecting the connective tissue surrounding the teeth leading to tooth loss. Pathogens associated with periodontitis interact with Toll-like receptors (TLRs) to induce cytokines causing and aggravating disease. We screened 197 individuals suffering from generalized periodontitis for the presence of Asp299Gly and Thr399Ile of TLR-4 as well as Arg753Gln of TLR-2 in comparison to matched controls. Single-nucleotide polymorphisms (SNPs) of TLR-4 were elevated among patients (odd's ratio 3.650, 95% CI 1.573-8.467, P < or = 0.0001), while no difference was observed for TLR-2. TLR-4 SNPs were correlated with chronic periodontitis (odd's ratio 5.562, 95% CI 2.199-14.04, P < or = 0.0001), but not with aggressive periodontitis. This observation was confirmed employing a group of periodontally healthy probands over 60 years of age. These data demonstrate that genetic variants of TLR-4 may act as risk factors for the development of generalized chronic periodontitis in humans.
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PMID:Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene. 1587 57

Periodontitis is a bacterially induced chronic inflammatory disease and a major cause of tooth loss in the world. The tissue damage and alveolar bone resorption characteristic of the disease are believed to be due to a destructive innate host response to a pathogenic subgingival biofilm. Porphyromonas gingivalis, a Gram-negative bacterium, is a member of this mixed microbial community that has been designated an etiologic agent of periodontitis. The innate host response to lipopolysaccharide (LPS) obtained from P. gingivalis is unusual in that different studies have reported that it can be an agonist for Toll-like receptor (TLR) 2 as well as an antagonist or agonist for TLR4. In addition, human monocytes respond to this LPS by secreting a variety of different inflammatory mediators, while endothelial cells do not. We have examined highly purified preparations of P. gingivalis LPS and found that they activate both TLR2 combined with TLR1 and TLR4 in transiently transfected human embryonic kidney (HEK) 293 cells. We have further demonstrated that highly purified P. gingivalis LPS preparations contain at least 3 major different lipid A species. We speculate that P. gingivalis lipid A structural heterogeneity contributes to the unusual innate host response to this LPS and its ability to interact with different TLR molecules.
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PMID:Porphyromonas gingivalis lipopolysaccharide displays functionally diverse interactions with the innate host defense system. 1601 14

Toll-like receptors (TLR) function as important signal transducers that mediate innate immune and inflammatory responses to pathogens through pattern recognition of virulence molecules. Although TLRs mediate protection against infection, it is also likely that they may have a pathophysiologic role in certain inflammatory diseases, such as atherosclerosis. In atherosclerotic lesions, endothelial cells and macrophages have been shown to upregulate TLR expression and may respond to TLR agonists of microbial origin, resulting in detrimental inflammatory reactions. Some of these potential TLR-activating virulence factors may be of oral origin. The detection in atherosclerotic plaques of DNA specific for Porphyromonas gingivalis and other periodontal pathogens suggests that these pathogens disseminate into the systemic circulation and localize in atheromas. The potential of periodontal and some other oral pathogens to activate TLRs in vivo is suggested by findings from cell culture experiments on interactions of selected virulence protein adhesins with TLRs and their coreceptors. Specifically, we have shown that proinflammatory cytokine induction by P. gingivalis fimbriae was inhibited by monoclonal antibodies to TLR2, TLR4, CD14, and beta2 integrins, but not by immunoglobulin isotype controls. Cytokine induction by Bacteroides forsythus protein A depended heavily on CD14 and TLR2. We also found that the ability of Streptococcus mutans protein AgI/II to stimulate cytokine release was partially dependent on CD14 and TLR4. Moreover, P. gingivalis fimbriae induced TLR-dependent activation of nuclear factor-kappaB and upregulation of costimulatory molecules in monocytic cells. These proinflammatory activities have been implicated in the pathogenesis of periodontitis, and similar inflammatory mechanisms could potentially operate in atherosclerosis. Studies by other groups have shown that P. gingivalis is capable of stimulating low-density lipoprotein oxidation, foam cell formation, and rupture of atherosclerotic plaque through induction of matrix metalloproteinases. Interestingly, at least some of these activities can be induced by TLR agonists (lipopolysaccharide and heat-shock protein-60) from Chlamydia pneumoniae, a major risk factor in atherosclerosis. Future research in animal models and in vitro cellular systems with defined mutations in TLRs may implicate TLR participation in oral pathogen-mediated atherosclerotic processes, thereby providing a mechanistic basis for the epidemiological findings linking oral pathogens to atherosclerotic disease.
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PMID:Interactions of oral pathogens with toll-like receptors: possible role in atherosclerosis. 1601 19

Bacterial deposits, smoking, and host genetic factors play a major role in an individual's predisposition to periodontitis. Bacterial components are recognized by CD14 and toll-like receptor 4 (TLR4), resulting in a NF-kappaB-based inflammatory response. We hypothesized that functional CD14 and TLR4 polymorphisms contribute to periodontitis susceptibility. We aimed to investigate the occurrence of CD14-260C>T, TLR4 299Asp>Gly, and 399Thr>Ile gene polymorphisms in adult periodontititis. DNA was collected from 100 patients with severe periodontitis and from 99 periodontally healthy controls. The gene polymorphisms were determined by the PCR technique. The presence of the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and whether the subjects smoked, was included in the analyses. The CD14-260T/T genotype was found in 34.0% of periodontitis patients and in 20.2% of controls. Logistic regression analysis adjusted for gender, age, smoking, and prevalence of P. gingivalis and A. actinomycetemcomitans showed an association between the CD14-260T/T genotype and periodontitis (P = 0.004, OR 3.0, 95% CI 1.4-6.9). We conclude that the CD14-260T/T genotype contributes to the susceptibility to severe periodontitis in Dutch Caucasians.
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PMID:CD14 and TLR4 gene polymorphisms in adult periodontitis. 1624 38

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