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)

Tissue factor (TF) is a transmembrane receptor which, in association with factors VII and VIIa, activates factor IX and X, thereby activating the coagulation protease cascades. In response to bacterial lipopolysaccharide (LPS) monocytes transcribe, synthesize and express TF on their surface. We investigated whether LPS-induced TF in human monocytes is mediated by protein kinase C (PKC) activation. The PKC agonists phorbol 12-myristate 13-acetate (PMA) and phorbol 12, 13 dibutyrate (PdBu) were both potent inducers of TF in human monocytes, whereas 4 alpha-12, 13 didecanoate (4 alpha-Pdd) had no such effect. Both LPS- and PMA-induced TF activity were inhibited, in a concentration dependent manner, by three different PKC inhibitors: H7, staurosporine and calphostin C. TF antigen determination confirmed that LPS-induced cell-surface TF protein levels decreased in parallel to TF functional activity under staurosporine treatment. Moreover, Northern blot analysis of total RNA from LPS- or PMA-stimulated monocytes showed a concentration-dependent decrease in TF mRNA levels in response to H7 and staurosporine. The decay rate of LPS-induced TF mRNA evaluated after the arrest of transcription by actinomycin D was not affected by the addition of staurosporine, suggesting that its inhibitory effect occurred at a transcriptional level. We conclude that LPS-induced production of TF and its mRNA by human monocytes are dependent on PKC activation.
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PMID:Endotoxin-induced tissue factor in human monocytes is dependent upon protein kinase C activation. 1101 86

Tissue factor (TF) is a transmembrane receptor that serves as the major cofactor for factor VIIa-catalyzed proteolytic activation of factors IX and X. In response to bacterial lipopolysaccharide (LPS), monocytes transcribe, synthesize, and express TF on their surface, thereby conveying to activated monocytes the ability to initiate the blood coagulation protease cascades. Agents that elevate cellular cyclic AMP (cAMP) inhibit the functional expression of TF by LPS-stimulated monocytes. In this study, we investigated the mechanism of this suppression. Northern blot analysis of total RNA from LPS-stimulated monocytes showed a concentration-dependent decrease in TF messenger RNA (mRNA) levels in response to dibutyryl-cAMP (dBt-cAMP). TF mRNA and procoagulant activity were inhibited as early as 1 hour after the addition of dBt-cAMP and the inhibition persisted through 4 hours. Suppression of specific mRNA abundance was also observed with agents, including forskolin and iso-butyl-methyl-xanthine (IBMX), that increase cAMP levels by independent mechanisms. Flow immunocytometric analysis confirmed that cell-surface TF protein levels declined in parallel with TF functional activity. The rate of decay of TF mRNA after the arrest of transcription by actinomycin D was not altered by the addition of dBt-cAMP, IBMX, or forskolin, thus excluding effects on TF mRNA stability. We conclude that elevated cAMP levels suppress TF mRNA by reducing the rate of TF gene transcription.
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PMID:Endotoxin-induced tissue factor messenger RNA in human monocytes is negatively regulated by a cyclic AMP-dependent mechanism. 767 11

Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll/IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll/IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.
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PMID:Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. 1100 52

Drosophila Toll protein is a transmembrane receptor whose function is to recognize the invasion of microorganisms as well as to establish dorso-ventral polarity. Recently, mammalian homologues of Toll, designated as Toll-like receptors (TLRs) have been discovered. So far, six members (TLR1-6) have been reported and two of these, TLR2 and TLR4, have been shown to be essential for the recognition of distinct bacterial cell wall components. TLR2 discriminates peptidoglycan (PGN), lipoprotein, lipoarabinomannan (LAM) and zymosan, whereas TLR4 recognizes lipopolysaccharide (LPS), lipoteichoic acid (LTA) and Taxol. Bacterial components elicit the activation of an intracellular signaling cascade via TLR in a similar way to that occurs upon ligand binding to IL-1 receptor (IL-1R). This signaling pathway leads to the activation of a transcription factor NF-kappaB and c-Jun N-terminal kinase (JNK), which initiate the transcription of proinflammatory cytokine genes. Particularly, analysis of knockout mice revealed a pivotal role for MyD88 in the signaling of the TLR/IL-1R family. Taken together, TLRs and the downstream signaling pathway play a key role in innate immune recognition and in subsequent activation of adaptive immunity.
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PMID:Toll-like receptors; their physiological role and signal transduction system. 1135 75

Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and allow scientists to investigate unique gene-environment interactions that are involved in the development of biologically specific forms of asthma.
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PMID:TLR4 and LPS hyporesponsiveness in humans. 1204 Sep 19

Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system elicits strong pro-inflammatory responses that can eventually cause a fatal sepsis syndrome in humans. LPS-mediated activation of mammalian cells is believed to involve the interaction of LPS with lipopolysaccharide-binding protein (LBP) in the serum and, subsequently with CD14. Although there is no doubt that CD14 binds LPS, CD14 is not capable of initiating a transmembrane activation signal because it is a glycosylphosphatidylinositol (GPI)-anchored protein. Accumulating evidence has suggested that LPS must interact with a transmembrane receptor(s) that is responsible for signal transduction. Integrins CD11c and/or CD18, Toll-like receptors (TLRs), as well as CD55, have been suggested to serve this function. Recently, we have revealed that a signalling complex of receptors is formed following LPS stimulation, which comprises heat-shock proteins (Hsps) 70 and 90, chemokine receptor 4 (CXCR4) and growth differentiation factor 5 (GDF5). Taking into account the discovery of the TLRs and the LPS-activation cluster, we propose a new model of LPS recognition.
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PMID:Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. 1207 69

Tissue factor (TF), a transmembrane receptor for plasma factor VII(a), is the main initiator of the coagulation cascade. It has also been implicated in noncoagulant processes, including inflammation. The function of the TF cytoplasmic domain was studied in mice in which 18 of the 20 cytoplasmic amino acids were deleted. This mutation (TF(deltaCT/deltaCT)) is not associated with alterations in blood coagulation. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in mice preimmunized with mBSA. Arthritis severity was significantly reduced in TF(deltaCT/deltaCT) mice compared to wild-type mice, including reductions in synovitis, synovial exudate, cartilage degradation, and bone damage. A marked reduction in synovial interleukin (IL)-1beta and IL-6 mRNA was also observed. Serum anti-mBSA IgG1, but not IgG2a, was increased in mutant mice. Cutaneous delayed-type hypersensitivity and antigen-induced T-cell proliferation were reduced in TF(deltaCT/deltaCT) compared to wild-type mice. A significant down-regulation of lipopolysaccharide-induced IL-1, tumor necrosis factor, IL-6, macrophage migration inhibitory factor, and matrix metalloproteinase-13 mRNA was observed in immunized, but not in naive TF(deltaCT/deltaCT) macrophages ex vivo. These data suggest a significant role for the cytoplasmic domain of TF in the regulation of the immunoinflammatory responses, a murine arthritis model, and macrophage function.
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PMID:Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice. 1469 25

Toll-like receptor (TLR)-4 is a transmembrane receptor for lipopolysaccharide, a highly pro-inflammatory component of the outer membrane of Gram-negative bacteria. To date, molecules of the TLR-4 signaling pathway have not been well characterized in cattle. The goal of this study was to clone and sequence the full-length coding regions of bovine genes involved in TLR-4 signaling including CASP8, IRAK1, LY96 (MD-2), TICAM2, TIRAP, TOLLIP and TRAF 6 and to position these genes, as well as MyD88 and TICAM1, on the bovine genome using radiation hybrid mapping. Results of this work indicate differences with a previously published bovine sequence for LY96 and a predicted sequence in the GenBank database for TIRAP based on the most recent assembly of the bovine genome. In addition, discrepancies between actual and predicted chromosomal map positions based on the Btau_2.0 genome assembly release were identified, although map positions were consistent with predicted locations based on the current bovine-human comparative map. Alignment of the bovine amino acid sequences with human and murine sequences showed a broad range in conservation, from 52 to 93%. Overall, this work should assist in the assembly and annotation of the bovine genome sequence, the identification of variations in genes critically involved in host innate immunity, and facilitate the study of TLR-4 signaling pathways in cattle.
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PMID:Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-4) signaling molecules. 1662 Oct 30

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.
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PMID:Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. 1670 4

Bacterial endotoxin (lipopolysaccharide - LPS) as one of the most potent inducers of the immune system is recognized by a complex cascade of extracellular "pattern recognition receptors", which chaperone the LPS from the bacterial membrane to the transmembrane receptor TLR4. Recent structural, biochemical and physiological investigations have advanced our understanding of the molecular pattern recognized by the receptors. The proposed mechanism of LPS recognition by the innate immune system involves as the first step binding of the LPS-binding protein (LBP) to LPS, which leads to a disruption of LPS aggregates Cationic amino acid residues at the tip of LBP play the most important role. The carboxyl-terminal domain of LBP, which interacts with CD14 or with the cell membrane, is required to streamline LPS signalling. The monomeric CD14:LPS complex is soluble, as the acyl chains of the lipid A are to a large extent protected from the solvent by interaction with the hydrophobic pocket of CD14. CD14 does not have a strong cationic cluster, characteristic of LBP and MD-2. Besides lipid A, CD14 recognizes also the carbohydrate chains of LPS and along with LBP governs the activation of the MyD88-independent signalling pathway of TLR4. The final cellular acceptor for LPS is MD-2, which comprises both a strong cationic and a hydrophobic binding site. MD-2 binds the LPS monomer and is sensitive to the acylation pattern of the lipid A moiety. Association of the MD-2:LPS complex to the ectodomain of Toll-like receptor 4 (TLR4) finally transduces the signal through the association of intracellular TIR domain, recruiting the adapter proteins triggering the signalling cascade.
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PMID:Structural biology of the LPS recognition. 1748 51


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