Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that infection with Chlamydia pneumoniae is associated with atherosclerosis, and that cytokines play an important role in the initiation and progression of Chlamydia-induced inflammation. When freshly isolated peripheral blood mononuclear cells (PBMC) were stimulated for 24 h with sonicated C. pneumoniae, significant amounts of the pro-inflammatory cytokines TNF-alpha and IL-1beta and of the anti-inflammatory cytokine IL-10 were released into the supernatant. The addition of serum increased cytokine release induced by C. pneumonia two- to fivefold (p < 0.01). This effect was not due to complement, mannose-binding lectin (MBL) or lipopolysaccharide-binding protein (LBP). Incubation of PBMC with either anti-Toll-like receptor 4 (TLR4) or anti-CD14 blocking antibodies did not influence the production of cytokines induced by Chlamydia. The induction of cytokines by C. pneumoniae in macrophages from C3H / HeJ mice, known to have a defective TLR4, was identical to that measured in control macrophages from C3H / HeN mice. In contrast, incubation of PBMC with an anti-TLR2 blocking antibody significantly inhibited the production of TNF by 67 % and of IL-1beta by 72 %. In conclusion, C. pneumoniae stimulates cytokine production in a serum-dependent manner, but independently of complement, MBL and LBP. C. pneumoniae induces the pro-inflammatory cytokines TNF and IL-1beta through TLR2, but not TLR4 and CD14.
 ...
PMID:Non-LPS components of Chlamydia pneumoniae stimulate cytokine production through Toll-like receptor 2-dependent pathways. 1193 27

Endothelial cells are activated by microbial agonists through Toll-like receptors (TLRs) to express inflammatory mediators; this is of significance in acute as well as chronic inflammatory states such as septic shock and atherosclerosis, respectively. We investigated mechanisms of lipopolysaccharide (LPS)-induced cell activation in human coronary artery endothelial cells (HCAEC) using a combination of FACS, confocal microscopy, RT-PCR, and functional assays. We found that TLR4, in contrast to TLR2, is not only located intracellularly but also functions intracellularly. That being the case, internalization of LPS is required for activation. We further characterized the HCAEC LPS uptake system and found that HCAEC exhibit an effective LPS uptake only in the presence of LPS binding protein (LBP). In addition to its function as a catalyst for LPS-CD14 complex formation, LBP enables HCAEC activation at low LPS concentrations by facilitating the uptake, and therefore delivery, of LPS-CD14 complexes to intracellular TLR4-MD-2. LBP-dependent uptake involves a scavenger receptor pathway. Our findings may be of pathophysiological relevance in the initial response of the organism to infection. Results further suggest that LBP levels, which vary as LBP is an acute phase reactant, could be relevant to initiating inflammatory responses in the vasculature in response to chronic or recurring low LPS.
 ...
PMID:Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses. 1513 88

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.
 ...
PMID:Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors. 1519 95

Recent studies suggest that inflammation plays a central role in the pathogenesis of atherosclerosis, and IFN-gamma is a prominent proinflammatory mediator in this context. However, it is unclear what stimuli are responsible for initial stimulation of IFN-gamma synthesis in the vessel wall. In the present study, we demonstrate that Chlamydia pneumoniae is an important stimulus for IFN-gamma synthesis, and this production depends on release of endogenous IL-18, IL-12, and IL-1, but not of TNF. The production of the proinflammatory cytokines TNF and IL-1beta from PBMC by sonicated C. pneumoniae was mediated through TLR2-dependent pathways. In contrast, C. pneumoniae stimulated the production of IL-18 through MyD88-dependent, TLR2-, TLR4-, and CD14-independent pathways, mediated by posttranscriptional mechanisms not involving de novo protein synthesis. In conclusion, C. pneumoniae is a potent stimulus of IFN-gamma production, in addition to the proinflammatory cytokines TNF and IL-1beta, which may contribute to its proatherogenic effects. Most interestingly, C. pneumoniae is also a potent inducer of IL-18 production through pathways independent of TLR2 and TLR4.
 ...
PMID:Chlamydia pneumoniae stimulates IFN-gamma synthesis through MyD88-dependent, TLR2- and TLR4-independent induction of IL-18 release. 1524 Jul 44

Chlamydophila pneumoniae, an obligately intracellular Gram-negative bacterium and a common causative agent of respiratory tract infections, has been implicated in the induction and progression of atherosclerosis and coronary artery disease. In this study, the signalling mechanism of C. pneumoniae in human fibroblasts, a prominent cell population in chronic inflammation and persistent infection, contributing to plaque formation, was investigated. C. pneumoniae elementary bodies were demonstrated to up-regulate the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK) in human fibroblasts. The effect was independent of the chlamydial lipopolysaccharide and was likely to be mediated by a heat-labile chlamydial protein. Furthermore, an anti-Toll-like receptor 4 (TLR4) antibody was shown to abolish C. pneumoniae-induced cell activation, whereas an anti-TLR2 antibody had no effect, indicating the role of TLR4 in p44/p42 MAPK activation. Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 and phosphodiesterase 4 (PDE 4) inhibitor Rolipram enhanced C. pneumoniae-induced MAPK phosphorylation and attenuated C. pneumoniae infectivity in vitro. Together the results indicate that C. pneumoniae triggers rapid TLR4-mediated p44/p42 MAPK activation in human fibroblasts and chemical enhancement of MAPK phosphorylation modulates in vitro infection at the molecular level.
 ...
PMID:Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4. 1558 96

ATP and ADP activate functionally distinct G protein-coupled purinergic (P2Y) receptors. We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells (hMCs). Human MCs expressed mRNA encoding the ADP-specific P2Y1, P2Y12, and P2Y13 receptors; the ATP/UTP-specific P2Y2 receptor; and the ATP-selective P2Y11 receptor. ADP (0.05-50 muM) induced calcium flux that was completely blocked by a P2Y1 receptor-selective antagonist and was not cross-desensitized by ATP. Low doses of ADP induced strong phosphorylation of ERK and p38 MAPKs; higher doses stimulated eicosanoid production and exocytosis. Although MAPK phosphorylation was blocked by a combination of P2Y1- and P2Y12-selective antagonists, neither interfered with secretion responses. Unexpectedly, both ADP and ATP inhibited the generation of TNF-alpha in response to the TLR2 ligand, peptidoglycan, and blocked the production of TNF-alpha, IL-8, and MIP-1beta in response to leukotriene D(4). These effects were mimicked by two ATP analogues, adenosine 5'-O-(3-thiotriphosphate) and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate (BzATP), but not by adenosine. ADP, ATP, adenosine 5'-O-(3-thiotriphosphate), and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate each induced cAMP accumulation, stimulated the phosphorylation of CREB, and up-regulated the expression of inducible cAMP early repressor, a CREB-dependent inhibitor of cytokine transcription. Human MCs thus express several ADP-selective P2Y receptors and at least one G(s)-coupled ADP/ATP receptor. Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis, tissue injury, and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs.
 ...
PMID:Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor. 1558 81

CD11b-CD18 and other integrins play important roles in immunity and inflammation and require prior activation through inside-out signaling to efficiently bind their ligands. We present evidence for a novel TLR2-dependent signaling pathway that leads to CD11b-CD18 activation in human monocytes or neutrophils upon recognition of Porphyromonas gingivalis fimbriae through CD14. The activated binding-state of CD11b-CD18, which involves induction of conformational changes, was monitored through detection of an activation-specific epitope of CD11b. The ability of fimbriae to induce this activation epitope was significantly inhibited by a mAb to TLR2, but not to TLR4 or unrelated surface molecules. Moreover, the ability of fimbriae to activate CD11b-CD18 was significantly inhibited by pharmacological inhibitors of phosphatidylinositol-3-kinase but not of PKC or of p38 mitogen-activated protein kinase. The signaling pathway activated by fimbriae is distinct from that which is activated by N-formyl-Met-Leu-Phe, a prototypical integrin activator, since the former was insensitive to pertussis toxin. This novel function of TLR2 as a signaling receptor for pathogen-induced activation of CD11b-CD18 may play a significant role in infection-driven chronic inflammatory conditions, such as periodontal disease or atherosclerosis, where P. gingivalis has been implicated.
 ...
PMID:Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase. 1573 63

Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.
 ...
PMID:Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. 1576 50

Proteasomes, multisubunit complexes that consist of a 20S proteasome and a 19S regulatory complex, are essential for several cellular processes. Our interest in the proteasome complex stems from our observations that a novel photoactivable lipopolysaccharide (LPS) probe binds to specific proteasome subunits, and that LPS enhances the chymotrypsin-like activity of the proteasome to degrade synthetic peptides in vitro. Experiments with proteasome inhibitors have shown that expression of many LPS-inducible genes, including TLR2, is inhibited in macrophages. More important, proteasome inhibitors such as lactacystin can prevent LPS-induced shock in mice. This article focuses on the role of the proteasome in the development of inflammatory processes, which may result in septic shock, hemorrhagic shock, atherosclerosis, and neurodegenerative disorders. Taken collectively, the results suggest a potentially important role of the proteasome in inflammation and other macrophage functions.
 ...
PMID:The proteasome: a central regulator of inflammation and macrophage function. 1588 15

TLR4 plays an important role in atherosclerosis, but little is known about the precise mechanism. Herein, we investigated the role of TLR4/NF-kappaB signaling pathway in monocyte-endothelial adhesion induced by low shear stress and Ox-LDL. We found that low shear stress up-regulated TLR4 expression in endothelial cells, and that ox-LDL exerted an obvious synergistic action as revealed by RT-PCR and Western blotting analysis. Low shear stress also significantly up-regulated IL-8 expression in endothelial cells. Meanwhile, NF-kappaB activity and the adhesion force of monocytes were increased, and there was a synergetic action of ox-LDL. However, following transfection with a functional mutant of TLR4 (C3H/HeJ, TLR4 Dicd) or addition of anti-human TLR4 mAb, IL-8 expression was obviously decreased, NF-kappaB activity in cells remarkably inhibited, and the adhesion force of monocyte significantly reduced. Nevertheless, anti-human TLR2 mAb had no similar effects. These findings suggest that TLR4 may be involved in the early stages of atherosclerosis, associating ox-LDL, inflammation/infection, and low shear stress. Therefore, TLR4 is expected to be a new target for preventing and treating atherosclerosis.
 ...
PMID:Role of Toll-like receptor 4/NF-kappaB pathway in monocyte-endothelial adhesion induced by low shear stress and ox-LDL. 1589 21


1 2 3 4 5 6 7 8 9 10 Next >>