Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human subjects consuming fish oil showed a significant suppression of cyclooxygenase-2 (COX-2) expression in blood monocytes when stimulated in vitro with lipopolysaccharide (LPS), an agonist for Toll-like receptor 4 (TLR4). Results with a murine monocytic cell line (RAW 264.7) stably transfected with COX-2 promoter reporter gene also demonstrated that LPS-induced COX-2 expression was preferentially inhibited by docosahexaenoic acid (DHA, C22:6n-3) and eicosapentaenoic acid (EPA, C20:5n-3), the major n-3 polyunsaturated fatty acids (PUFAs) present in fish oil. Additionally, DHA and EPA significantly suppressed COX-2 expression induced by a synthetic lipopeptide, a TLR2 agonist. These results correlated with the preferential suppression of LPS- or lipopeptide-induced NF kappa B activation by DHA and EPA. The target of inhibition by DHA is TLR itself or its associated molecules, but not downstream signaling components. In contrast, COX-2 expression by TLR2 or TRL4 agonist was potentiated by lauric acid, a saturated fatty acid. These results demonstrate that inhibition of COX-2 expression by n-3 PUFAs is mediated through the modulation of TLR-mediated signaling pathways. Thus, the beneficial or detrimental effects of different types of dietary fatty acids on the risk of the development of many chronic inflammatory diseases may be in part mediated through the modulation of TLRs.
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PMID:Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. 1256 75

I kappa B-zeta, a new negative-regulator of nuclear factor-kappa B (NF-kappa B), is strongly induced by lipopolysaccharide or interleukin-1 beta stimulation, but not by tumor necrosis factor-alpha. Here, we analyzed the mechanisms for transcriptional induction of I kappa B-zeta. I kappa B-zeta mRNA was induced by overexpression of MyD88 or TRAF6, but not TRAF2. Stimulation of macrophages with peptidoglycan or CpG DNA, which activated Toll-like receptor 2 or 9, respectively, also resulted in I kappa B-zeta induction. Thus, activation of the MyD88-dependent signaling pathway, commonly found downstream of different Toll/interleukin-1 receptor (TIR) domains, is sufficient for I kappa B-zeta induction. The induction was inhibited by treatment with various inhibitors of NF-kappa B activation or by overexpressing I kappa B-alpha or beta, indicating essential roles for NF-kappa B in I kappa B-zeta induction. However, overexpression of the NF-kappa B subunits induced I kappa B-alpha, but not I kappa B-zeta. These results indicate the existence of another signal essential for I kappa B-zeta induction, which is specifically mediated by the TIR domain-mediated signaling pathway.
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PMID:Essential roles for NF-kappa B and a Toll/IL-1 receptor domain-specific signal(s) in the induction of I kappa B-zeta. 1256 89

We compared human periodontal ligament fibroblasts with human gingival fibroblasts isolated from the same donor to examine interleukin-8 (IL-8) responses of the cells to Salmonella lipopolysaccharide, a water-soluble peptidoglycan from Staphylococcus epidermidis and the synthetic muramyldipeptide, with special reference to the possible involvement of the CD14/Toll-like receptor (TLR) system of the cells in the responses. Human gingival fibroblasts expressed CD14 on their surfaces and strongly expressed CD14 mRNA, while human periodontal ligament fibroblasts showed considerably lower levels of expression in both respects. Both cells expressed mRNA of TLR-related molecules, i.e. TLR2, TLR4, MD-2 and MyD88, although human periodontal ligament fibroblasts expressed TLR2 more strongly than human gingival fibroblasts. Human gingival fibroblasts exhibited a stronger IL-8 response than human periodontal ligament fibroblasts to lipopolysaccharide, while human periodontal ligament fibroblasts exhibited a response comparable to, or slightly stronger than, that of human gingival fibroblasts to S. epidermidis peptidoglycan and muramyldipeptide. The IL-8 responses of both cells to lipopolysaccharide and S. epidermidis peptidoglycan were completely inhibited by antihuman CD14 monoclonal antibody (MAb). The responses of both cells to lipopolysaccaride were significantly inhibited by antihuman TLR4 MAb, while those to S. epidermidis peptidoglycan were inhibited by antihuman TLR2 MAb. In contrast, muramyldipeptide activated both types of cells in a TLR2- and TLR4-independent manner, although the activities of muramyldipeptide on human gingival fibroblasts, but not human periodontal ligament fibroblasts, were significantly inhibited by anti-CD14 MAb.
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PMID:Contrasting responses of human gingival and periodontal ligament fibroblasts to bacterial cell-surface components through the CD14/Toll-like receptor system. 1258 54

Lipopolysaccharide (LPS) induces neutrophils to synthesize and secrete pro-inflammatory cytokines and chemokines, which are regulated at both the transcriptional and translational level. We reported previously that neutrophils stimulated with LPS induce expression of genes typically expressed in response to stimulation with antiviral type I interferons (IFN), such as myxovirus resistance-1 (MX1). However, we present evidence that this response of neutrophils to lipopolysaccharide occurs in the absence of interferon-dependent signaling. Lipopolysaccharide-stimulated neutrophils do not phosphorylate the interferon-associated transcription factors signal transducer and activator of transcription-1 and -3, and medium from lipopolysaccharide-stimulated cells was unable to induce MX1 gene expression, suggesting a soluble factor is not involved. Furthermore, LPS did not alter expression of IFNA and IFNB genes. In contrast to neutrophils, LPS-stimulated human monocyte-derived macrophages induced the expression of MX1, but IFNB was induced, and medium from LPS-stimulated monocyte-derived macrophages supported MX1 induction. An inhibitor of p38 kinase blocked induction of MX1 by lipopolysaccharide, but not IFNalpha, in neutrophils, and induction of MX1 was dependent on protein synthesis. LPS, but not IFNalpha, substantially activated p38. In contrast, the induction of MX1 by LPS in monocyte-derived macrophages was insensitive to p38 inhibition, although p38 is phosphorylated in LPS-stimulated but not IFNalpha-stimulated monocyte-derived macrophages. The expression of MX1 in neutrophils and monocyte-derived macrophages is mediated by TLR4 but not TLR2. The data presented here indicate that lipopolysaccharide activates novel interferon-independent signaling pathways in neutrophils and that induction of antiviral genes is a consequence of exposure of neutrophils to bacterial products.
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PMID:Lipopolysaccharide stimulates p38-dependent induction of antiviral genes in neutrophils independently of paracrine factors. 1259 30

All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.
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PMID:Molecular insights on the cerebral innate immune system. 1261 45

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), which are found in the cell walls of gram-negative and gram-positive bacteria, respectively. This study was conducted to determine if TLRs are present on chicken heterophils and if these receptors mediate oxidative burst. Heterophils isolated from neonatal chicks were exposed to gram-negative Salmonella enteritidis (SE), gram-positive Staphylococcus aureus (SA), SE-LPS, and SA-LTA and the oxidative burst quantitated by luminol-dependent chemiluminescence. SE, SA, SE-LPS, and SA-LTA stimulated a significant increase in oxidative burst from heterophils. Furthermore, we measured the inhibitory effects of polyclonal antibodies on rat CD14, human TLR2 and TLR4 on the oxidative burst of heterophils when stimulated with LPS and LTA. The data suggest that TLR2 and TLR4 mediate LPS-stimulated oxidative burst while CD14 and TLR2 mediate LTA-stimulated oxidative burst in heterophils. This is the first report of PAMPs from gram-positive and gram-negative bacteria interacting with TLRs of avian heterophils.
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PMID:Oxidative burst mediated by toll like receptors (TLR) and CD14 on avian heterophils stimulated with bacterial toll agonists. 1263 24

Toll-like receptors (TLRs) are involved in mediating cell activation on stimulation with microbial constituents. We investigated the role for TLRs in synovial fibroblast (SF) activation in rheumatoid arthritis (RA). We analyzed whether stimulation with interleukin-1 beta and tumor necrosis factor-alpha, cytokines present in RA synovium, influences expression of TLR genes in SFs. The effects were compared with those of treatment with lipopolysaccharide and a synthetic lipopeptide (sBLP). Gene expression was examined using quantitative polymerase chain reaction. TLR2-mediated cell activation was investigated by electromobility shift assay for nuclear factor-kappa B. To localize TLR2 expression in joint tissue sections of RA patients were stained using in situ hybridization. Expression of TLR2 in RA SFs was increased after treatment with interleukin-1 beta, tumor necrosis factor-alpha, lipopolysaccharide, and sBLP. Nuclear factor-kappa B translocation in SFs was triggered by TLR2-mediated cell stimulation. Synovial tissues from RA joints expressed TLR2 predominantly at sites of attachment and invasion into cartilage and bone. The observed elevated expression of TLR2 in RA SFs could be a consequence of direct exposure to microbial compounds or of the presence of inflammatory mediators in the joint. TLR-associated signaling pathways may contribute to the pathogenesis of RA, either by initiating or perpetuating activation of SFs.
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PMID:Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. 1265 14

In the present report we have analyzed whether human normal cord blood-derived mast cells (CBMC) could interact with bacterial products, especially lipopolysaccharide (LPS) from Escherichia coli and peptidoglycan (PGN) from Staphylococcus aureus, known as Toll-like receptor (TLR) 4 and TLR2 agonists, respectively. We found that both LPS and PGN induced significant release of not only tumor necrosis factor-alpha (TNF-alpha), but also IL-5, IL-10 and IL-13 by human mast cells (MC). We also established that the stimulation of CBMC with LPS or with PGN is mediated through interactions with TLR4 or with TLR2, respectively. Thus, our data indicate that activation of either TLR2 or TLR4 pathway may lead to a pro-Th2 immune response. However, the release of TNF-alpha induced by LPS, conversely to PGN, required the priming of CBMC by IL-4 and the presence of serum components, in particular soluble CD14. Of interest, stimulation by PGN, but not by LPS, induced release of histamine by human MC. Altogether, these findings provide the first evidence that human MC differentially respond towards bacterial components, and that their responses depend on TLR pathways and reveal human specificities in the pattern of cytokine production.
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PMID:Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. 1267 55

Gene- and signal-specific adaptation/tolerance of blood leukocytes to lipopolysaccharide endotoxin (LPS) occurs during human and animal septicemia. These phenotypes can be modeled in vitro. LPS-TLR4-adapted human THP-1 promonocytic cells cross-adapt to lipoteichoic acid (LTA)-TLR2-induced IL-1beta/TNF-alpha production, suggesting disruption of a common intracellular signaling event(s). A plausible explanation for homologous adaptation of TLR4 with heterologous adaptation of TLR2 is a persistent inactivation and degradation of IRAK1 following TLR4 activation. LTA stimulation of TLR2 also produces homologous adaptation of TLR2 with inactivation of IRAK1, but there is no detectable degradation of IRAK1. Strikingly, such LTA-adapted cells still respond to LPS stimulation of TLR4 with rapid activation and degradation of IRAK1, and robust IL-1beta/TNF-alpha production. Moreover, cells adapted to either LTA- or LPS-production of IL-1beta/TNF-alpha normally produce soluble interleukin 1 receptor antagonist (sIL-1Ra) anti-inflammatory protein when stimulated by either agonist. We conclude that: (i) disruption of a unique TLR2 signaling component upstream of IRAK1, but downstream of TLR2 sensing, induces homologous adaptation to LTA; (ii) disruption of IRAK1 may induce homologous adaptation of TLR4 to LPS and cross-adaptation of TLR2 to LTA; and (iii) TLR2/TLR4 signaling events that control sIL-1Ra translation do not adapt to LPS or LTA, indicating that TLR4 and TLR2 can still function. We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly.
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PMID:Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. 1269 17

Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mononuclear cells. Assessment of NF-kappa B activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-kappa B p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-alpha and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.
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PMID:Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A. 1270 21


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