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)

An injection of Escherichia coli lipopolysaccharide (LPS) increased the activity of histidine decarboxylase (HDC) in bone marrow (BM) cells of C3H/HeN mice much more than in C3H/HeJ mice, which are resistant to various effects of LPS. In WBB6/F1 (W/Wv) mice, which are genetically deficient in mast cells, HDC activity increased more than in C3H/HeN mice. Cultured BM cells of W/Wv mice spontaneously synthesized histamine in a HDC-dependent way. LPS caused a slight increase in HDC-associated histamine synthesis by these cells. Treatment of the BM cells with murine recombinant granulocyte-macrophage colony stimulating factor (mrGM-CSF) increased the histamine synthesis. In addition, treatment with mrGM-CSF made the cells respond to LPS by a dose-dependent increase in HDC activity and histamine synthesis. Most dish-adherent BM cells that had been treated with both mrGM-CSF and LPS for 48 h were stained for nonspecific esterase and not for chloroacetate esterase, and had twice as much HDC activity as the nonadherent cells had. Immunocytochemical analysis of the BM cells of W/Wv mice treated with both mrGM-CSF and LPS showed that HDC was in the cytoplasm of cells having Mac-1, a macrophage-differentiation antigen. These results suggest that cells of the macrophage lineage in the BM of mice synthesize histamine.
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PMID:Histamine synthesis by cells of the macrophage lineage in bone marrow of mice. 754 1

In vitro studies have previously shown that the myelomonocytic differentiation antigen CD14 is a receptor for a complex consisting of lipopolysaccharide (LPS) and LPS-binding protein. To investigate the role of CD14 in vivo and its relationship to induction of LPS-induced endotoxin shock, transgenic mice expressing human CD14 were produced. These mice express human CD14 strongly on the surface of their monocytes, neutrophils, and Thy-1(+) lymphocytes and are hypersensitive to LPS, as evidenced by their increased susceptibility to endotoxin shock. These results document the importance of CD14 in vivo as a primary mediator of this lethal syndrome. Furthermore, these mice provide an important model for testing the therapeutic effects of agents directed specifically against the human, as opposed to the murine, CD14 protein in preventing LPS-induced endotoxin shock.
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PMID:Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide. 768 94

The myeloid differentiation antigen CD14 acts as the major receptor for bacterial lipopolysaccharide (LPS). A soluble form of the protein (sCD14) is present in human serum which functions as a soluble LPS receptor. We have compared the isoform patterns of soluble CD14 derived from human serum and of the recombinant proteins produced by CHO cells transfected with either the wild-type CD14 gene or with a cDNA coding for a truncated protein which lacks the C-terminal 21 amino acids [sCD14-(1-335)-peptide]. Using SDS/PAGE, two dominant isoforms (53 and 50 kDa) and two minor forms (46 and 43 kDa) can be detected in serum as well as in the supernatants of both transfectants. sCD14 is a glycoprotein which carries N- and O-linked carbohydrates. The different isoforms of sCD14-(1-335)-peptide are due to differences in the content of N-linked sugars. However after the removal of N- and O-linked carbohydrates from serum- and CHO-derived wild-type proteins, two isoforms are still present. These results indicate that N-linked glycosylation contributes to but does not fully explain the different forms of soluble CD14. We further examined whether the mutation of individual N-linked glycosylation sites influences the expression of membrane-bound and soluble CD14 forms and the ability of the membrane-bound molecule to bind LPS. As with the wild-type proteins, the different isoforms of the soluble mutants are partially due to differences in N-linked glycosylation. A truncated mutant which lacks the two N-terminal glycosylation sites {[Asp18, Asp132]CD14-(1-335)peptide} does not give rise to multiple forms on SDS gels. Like CD14-(1-335)-peptide, this mutant is not expressed on the cell surface suggesting that a smaller isoform present in the wild-type preparations results from proteolytic cleavage of the membrane-bound molecule. N-linked carbohydrates do not seem to be important for the binding of LPS to membrane-bound CD14.
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PMID:The myeloid differentiation antigen CD14 is N- and O-glycosylated. Contribution of N-linked glycosylation to different soluble CD14 isoforms. 861 16

CD14, a 55kDa glycoprotein, serves as a lipopolysaccharide (LPS) recognition molecule. CD14 is a monocyte differentiation antigen expressed by myeloid-derived cells, or other cells such as hepatocytes, as either a membrane-bound protein or a soluble serum protein. Increasing evidence indicates that soluble CD14 in plasma is an acute-phase protein derived, among other sources, from liver cells. Although information is available on the cellular expression of CD14, little is known about the cis- and trans-acting factors that regulate basal CD14 transcription in liver cells. We show here that liver cells have a relatively high basal CD14 transcription rate as determined by nuclear run-on assay. We cloned and sequenced an 883bp 5'-flanking region of the rat CD14 gene and demonstrated functional promoter activity in liver cells. Sequence analysis revealed that, like in the human and mouse CD14 genes, multiple Sp1 and AP1 binding elements exist in rat CD14. Site-directed mutagenesis and transient transfection assays demonstrated that an Sp1 element located at -836 and an AP1 element located at -270 are required for basal promoter activity in liver cells. Electrophoretic mobility shift assays indicate that both Sp1 and Sp3 nuclear factors interact with the -836 Sp1 element, while the AP1-related proteins Fra-2 and JunD bind to the AP1 motif. These data provide novel insights into the regulation of basal CD14 expression in liver cells.
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PMID:Characterization of rat CD14 promoter and its regulation by transcription factors AP1 and Sp family proteins in hepatocytes. 1085 87

Induced prostanoid synthesis by cells associated with the cerebral vasculature has been implicated in mediating immune system influences on the CNS, but the cell type(s) involved remain unsettled. To determine whether this might derive from differences in the nature and intensity of the stimuli used to model immune insults, immunochemical and hybridization histochemical methods were used to monitor cyclooxygenase-2 (COX-2) expression alone, or in conjunction with endothelial, perivascular, and glial cell markers, in brains of rats treated with varying doses of interleukin-1 (IL-1) or bacterial lipopolysaccharide (LPS). Vehicle-treated animals displayed weak COX-2 expression in the meninges, choroid plexus, and larger blood vessels. Rats challenged intravenously with IL-1beta (1.87-30 microgram/kg) showed a marked increase in the number of vascular-associated cells displaying COX-2-immunoreactivity (ir). More than 90% stained positively for the ED2 macrophage differentiation antigen, identifying them as perivascular cells, whereas none coexpressed endothelial or glial cell markers. Low doses of LPS (0.1 microgram/kg) elicited a similar response profile, but higher doses (2-100 microgram/kg) provoked COX-2 expression in a progressively greater number of cells exhibiting distinct round or multipolar morphologies, corresponding to cells expressing endothelial (RECA-1) or perivascular (ED2) cell antigens, respectively. Similarly, ultrastructural analysis localized COX-2-ir to the perinuclear region of endothelial cells of LPS-treated but not IL-1-treated rats. We conclude that perivascular cells exhibit the lower threshold to COX-2 expression in response to either IL-1 or endotoxin treatment, and that enzyme expression by endothelial cells requires one or more facets of the more complex immune stimulus presented by LPS.
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PMID:Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. 1209 12

Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-alpha) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to determine the mechanisms involved in its regulation. At a high concentration of LPS (10 ng/ml) and in the presence of autologous plasma, MNC from adults and newborns secreted similar amounts of TNF-alpha. However, in the absence of plasma, MNC from newborns secreted significantly less TNF-alpha compared to MNC from adults. Moreover, at a low concentration of LPS (0.1 ng/ml) and in the presence of plasma, TNF-alpha secretion was significantly lower for newborn MNC compared to adult MNC. Adults and newborns had similar numbers of CD14 and Toll-like receptor 4 (TLR-4)-positive cells as measured by flow cytometry. However, the intensity of the CD14 marker was greater for adult than for newborn cells. Incubation of cells with LPS led to an increase in CD14 and TLR-4 intensity for adult cells but not for newborn cells. The effect of LPS stimulation of adult or newborn cells was similar for ERK, p38, and IkappaBalpha phosphorylation, as well as IkappaBalpha degradation. Finally, we assessed levels of the TLR-4 adapter protein, the myeloid differentiation antigen 88 (MyD88). We found a direct relation between adult and newborn TNF-alpha secretion and MyD88, which was significantly decreased in newborn monocytes. Since TLR-4 signals intracellularly through the adapter protein, MyD88, we hypothesize that MyD88-dependent factors are responsible for delayed and decreased TNF-alpha secretion in newborn monocytes.
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PMID:Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. 1497 22

Three-dimensional microlocalization of adhesion molecules, i.e. ICAM-1 (intercellular adhesion molecule), VCAM-1 (vascular adhesion molecule), LFA-1 (lymphocyte function-associated antigen), Mac-1 (macrophage differentiation antigen) and VLA-4 (very late activation antigen), expressed on type-A synoviocyte (macrophage-like cell) and type-B synoviocyte (fibroblast-like cell), were detected by immuno-scanning electron microscopy (SEM) to investigate the immunoreactive microenvironment of the superficial synovial intima in lipopolysaccharide (LPS)-induced arthritis of the mouse knee. Type-B synoviocytes extended rich slender processes from the periphery and constructed a cytoplasmic network, to which ICAM-1 was restricted. VCAM-1 was expressed only in the LPS-stimulated group and was relatively limited to the microvilli of type-B synoviocytes. Type-A synoviocytes were located randomly among the network with a smoother surface and expressed Mac-1 and LFA-1, which were counter-receptors for ICAM-1, and VLA-4 for VCAM-1 on the microvilli or lamellipodia. Three-dimensional microlocalization of adhesion molecules suggests that the network constructed by cytoplasmic processes and microvilli of type-B synoviocytes forms the pathway for the migration or the foothold for the fixation of type-A synoviocytes and takes part in forming an immunoreactive environment in the articular cavity.
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PMID:Three-dimensional expression of adhesion molecules on the superficial synovial intima of LPS-induced arthritis of the mouse knee analyzed by immuno-SEM. 1507 4

Alveolar macrophages (AMs) normally respond to lipopolysaccharide (LPS) by activating Toll-like receptor (TLR)-4 signaling, a mechanism critical to lung host defense against gram-negative bacteria such as Pseudomonas aeruginosa. Because granulocyte macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)) mice are hyporesponsive to LPS, we evaluated the role of GM-CSF in TLR-4 signaling in AMs. Pulmonary TNF-alpha levels and neutrophil recruitment 4 h after intratracheal administration of Pseudomonas LPS were reduced in GM(-/-) compared with wild-type (GM(+/+)) mice. Secretion of TNF-alpha by AMs exposed to LPS ex vivo was also reduced in GM(-/-) mice and restored in mice expressing GM-CSF specifically in the lungs (SPC-GM(+/+)/GM(-/-) mice). LPS-dependent NF-kappaB promoter activity, TNF-alpha secretion, and neutrophil chemokine release were reduced in AM cell lines derived from GM(-/-) mice (mAM) compared with GM(+/+) (MH-S). Retroviral expression of PU.1 in mAM cells, which normally lack PU.1, rescued all of these AM defects. To determine whether GM-CSF, via PU.1, regulated expression of TLR-4 pathway components, mRNA and protein levels for key components were evaluated in MH-S cells (GM(+/+), PU.1(Positive)), mAM cells (GM(-/-), PU.1(Negative)), and mAMPU.1+ cells (GM(-/-), PU.1(Positive)). Cluster of differentiation antigen-14, radioprotective 105, IL-1 receptor-associated kinase (IRAK)-M mRNA, and protein were dependent upon GM-CSF and restored by expression of PU.1. In contrast, expression of other TLR-4 pathway components (myeloid differentiation-2, TLR-4, IRAK-1, IRAK-2, Toll/IL-1 receptor domain containing adapter protein/MyD88 adaptor-like, myeloid differentiation primary-response protein 88, IRAK-4, TNF receptor-associated factor-6, NF-kappaB, inhibitor of NF-kappaB kinase) were not GM-CSF or PU.1-dependent. These results show that GM-CSF, via PU.1, enables AM responses to P. aeruginosa LPS by regulating expression of a specific subset of components of the TLR-4 signaling pathway.
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PMID:GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. 1691 76

The term sepsis describes a potentially lethal clinical condition that develops as a result of a dysregulated host response to bacterial infection. The most common bacterial component implicated in initiating the septic syndrome is a cell wall molecule derived from Gram-negative bacteria, known as lipopolysaccharide (LPS) or endotoxin. Like all mammals, humans are equipped with an LPS-sensing machinery consisting, primarily, of LPS-binding protein (LBP), CD14, a glycosylphosphatidylinositol (GPI)-anchored monocyte differentiation antigen, and toll-like receptor 4 (TLR4), a signal-transducing integral membrane protein. Modest stimulation of TLR4 facilitates the elimination of invading microorganisms. Potent TLR4 stimulation, however, produces severe reactions in the host, often leading to multiple organ failure and death. The search for pharmaceuticals that reduce mortality in septic patients has been a painstaking process. Thus far, only a few compounds have been found to significantly reduce mortality rates. Perhaps one of the more promising therapeutic strategies currently pursued is based on the identification of synthetic or naturally occurring substances that neutralize LPS or inhibit LPS-mediated activation of host immune cells, such as monocytes and macrophages. Here, we describe a number of diverse molecular structures with a capacity to either enhance or blunt LPS-induced monocyte activation. The underlying molecular mechanisms are discussed.
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PMID:Targeting bacterial endotoxin: two sides of a coin. 1740 10

CD14 is a surface differentiation antigen that functions as a receptor for bacterial lipopolysaccharide. The cellular signaling events that lead to lipopolysaccharide-induced production of inflammatory mediators are the primary cause of myocardial dysfunction observed in sepsis. Here, we evaluated the role of CD14 in chick embryo cardiomyocytes stimulated with lipopolysaccharide. CD14 expression was detected by confocal laser microscopy observation and by immunoblotting analysis. Moreover, we provided evidence for CD14-dependent functional responses of lipopolysaccharide-stimulated cardiomyocytes in terms of tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. Attenuated TNF-alpha and NO secretion, following anti-CD14 treatment of cardiomyocytes, suggested a role for this receptor in lipopolysaccharide-mediated cell responses. We also evidenced that labeled lipopolysaccharide was internalized and localized next to the Golgi complex, at the level of lysosomes, and in the perinuclear zone. The intracytoplasmatic transport seems to depend on the contractile apparatus, because cell pretreatment with cytochalasin D prevented lipopolysaccharide internalization and reduced both TNF-alpha and NO release. Lipopolysaccharide internalization was dependent on CD14 receptor, since anti-CD14 pre-treatment prevented endotoxin uptake by cardiomyocytes. Results demonstrated: (1) CD14 is expressed on the surface membrane of cardiomyocytes; (2) CD14 is involved in cytoskeletal dependent lipopolysaccharide internalization at specific cytoplasmatic locations; (3) CD14 plays a role in lipopolysaccharide-mediated responses by cardiomyocytes after lipopolysaccharide internalization.
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PMID:CD14 major role during lipopolysaccharide-induced inflammation in chick embryo cardiomyocytes. 1835 91


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