Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031099 (periodontitis)
 12,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

LPS of Porphyromonas gingivalis (P. gingivalis) is suggested to be a virulence factor in periodontitis, stimulating host cells to produce proinflammatory mediators. However, P. gingivalis LPS has been reported to show lower biological activity compared with Escherichia coli (E. coli) LPS. Although differences in the chemical structure of lipid A and the receptor conferring LPS signaling are thought to account for these characteristics, the precise reason is unknown. Here, we demonstrate that P. gingivalis LPS up-regulates IL-1R-associated kinase (IRAK)-M, a negative regulator of the TLR signaling pathway, in a THP-1-derived macrophage more robustly than E. coli LPS. Although down-regulation of IRAK-M by small interfering (si)RNA augmented transcription and translation of TNF-, IL-6, and IL-12 p40 in LPS-stimulated macrophages, the effect of siRNA was more prominent in P. gingivalis LPS-stimulated cells. Degradation of IRAK-1 was more obvious in E. coli LPS-stimulated macrophages than the cells stimulated with P. gingivalis LPS, suggesting that P. gingivalis LPS-induced IRAK-M suppressed dissociation of IRAK-1 from the receptor complex, resulting in escape from subsequent degradation. This activity may be involved in the chronic infection of this bacterium in periodontal tissue by serving as an escape mechanism from immune surveillance.
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PMID:Early and preferential induction of IL-1 receptor-associated kinase-M in THP-1 cells by LPS derived from Porphyromonas gingivalis. 1815 87