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)

We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal-associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur within 1-2 d and are irreversible, since neither pinocytosis nor the class II compartment are recovered when the maturation-inducing stimulus is removed. The specificity of the MR and the capacity to respond to inflammatory stimuli maximize the capacity of DCs to present infectious non-self antigens to T cells.
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PMID:Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. 762 94

Two carbohydrate-dependent mechanisms exist on alveolar macrophages to clear mannose-containing pathogens: receptor-mediated entry of non-opsonized microorganisms via the mannose receptor and receptor recognition of pathogens opsonized with surfactant-associated protein A (SP-A). A number of studies have demonstrated that mannose receptor expression is tightly linked to the functional state of the macrophage. In the present study, we investigated regulation of binding of SP-A to its receptor on macrophages by the same agents that regulate mannose-receptor expression. Phorbol 12-myristate 13-acetate, lipopolysaccharide (LPS), and interferon-gamma treatment of rat marrow-derived macrophages increased SP-A binding by 163, 296, and 337%, respectively, over untreated controls. Mannose-receptor activity was reduced to 75, 60, and 25% of control levels by these agents. Dexamethasone increased mannose receptor activity to 225%, while decreasing SP-A binding to 44% of controls. Addition of granulocyte macrophage-colony stimulating factor (GM-CSF) to human monocytes on day 0 dramatically increased mannose-receptor activity on day 5 over the non-serum control. SP-A binding was highest to freshly isolated monocytes and decreased to < 10% after differentiation in the presence of GM-CSF. After intraperitoneal injection of dexamethasone, rat alveolar macrophages isolated at 24 h expressed increased mannose-receptor activity and decreased SP-A binding. LPS injection resulted in increased SP-A binding and decreased mannose-receptor activity. In every instance, SP-A binding was inversely regulated with respect to mannose-receptor expression. We therefore speculate that the mannose receptor is a first-line host-defense receptor that is turned off during inflammation. SP-A in the alveolar space can then act as a lung-specific opsonin and mediate clearance of pathogens via the upregulated SP-A receptor.
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PMID:Differential regulation of the mannose and SP-A receptors on macrophages. 857 33

Using fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC), 125I-mannan, or 125I-invertase as specific ligands for the mannose receptor, we have quantified its activity in mouse and rat hepatic sinusoidal endothelium (HSE), under both basal conditions and after lipopolysaccharide (LPS) or human recombinant interleukin-1beta (IL-1beta) stimulations. Mouse treatment for 4 hours with 5 microg/kg IL-1beta significantly increased OVA-FITC uptake by HSE. Ligand uptake exhibited a sublobular compartmentalization: In control mice as well as in IL-1beta-stimulated mice, the ligand distributed preferentially in the periportal and septal areas; no OVA-FITC was observed in the perivenous sinusoids. In vitro exposure of mouse HSE to 100 pg/mL LPS or 1 ng/mL IL-1beta for 6 hours significantly (P < .01) increased OVA-FITC uptake. Blocking IL-1 receptors in HSE by addition of 100 ng/mL IL-1 receptor antagonist (IL-1Ra) before stimulation with LPS or IL-1beta abrogated the increase in mannose receptor-mediated uptake. In vitro endocytosis assays showed that rat HSE uptake of 125I-mannan or 125I-invertase progressively increased with both exposure time and concentration of added IL-1beta. Upregulation of mannose receptor-mediated uptake in response to IL-1beta or LPS was also blocked by previous addition of IL-1Ra to rat HSE. Flow cytometric analysis showed a significant HSE heterogeneity in mannose receptor-mediated endocytosis in response to IL-1beta treatment: type I endothelial cells (EC-I, defined by their small size and high cytoplasmic density) significantly (P < .01) increased OVA-FITC uptake compared with type II endothelial cells (EC-II, defined by their large size and low cytoplasmic density). In addition, the subset of EC-I contained three times more IL-1beta-binding cells than the EC-II subset. Because EC-I and EC-II are preferentially located in the periportal and perivenous segments of hepatic sinusoids, respectively, these results suggest that IL-1beta, apart from upregulating mannose receptor activity, contributes to the sublobular compartmentalization of this endothelial cell function.
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PMID:Hepatic sinusoidal endothelium heterogeneity with respect to mannose receptor activity is interleukin-1 dependent. 867 73

Recently we developed mouse monoclonal antibodies (mAb) against the isolated human 175-kDa mannose receptor. In the present study we tested whether these mAb are suitable for the detection of the mannose receptor on cultured macrophages using flow cytometry and on cells in human tissues using immunohistochemistry. Human monocytes did not react with the mAb in flow cytometry. Mannose receptor expression became detectable on monocytes cultured for 3 days (macrophages), and was maximal from 4 days onward. The mannose receptor was up-regulated on dexamethasone-treated (immunosuppressed) macrophages, and down-regulated on lipopolysaccharide-treated (activated) macrophages. Immunohistochemically the staining pattern of our mAb was compared with the marker of monocytes/macrophages KP1. In a bone marrow smear, only macrophages were stained with our mAb, whereas all myeloid cells were stained with KP1. In the thymus and lymph node, mannose receptor-positive branched cells (macrophages and dendritic cells) were detected in connective tissue, thymus cortex (not medulla), and in the T cell area (not the B cell area) of lymph nodes, whereas KP1 stained branched cells in all areas. It was concluded that the mAb are useful tools in flow cytometry and immunohistochemistry for the specific detection of cells expressing mannose receptor.
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PMID:Monoclonal antibodies against the human mannose receptor as a specific marker in flow cytometry and immunohistochemistry for macrophages. 900 May 38

We found that surfactant protein A (SP-A) enhances phagocytosis of Klebsiella pneumoniae K21a but not of K2 serotypes by alveolar macrophages. SP-A interacted with the capsule of K21a (containing Man alpha1 Man sequences) as shown by SP-A-induced agglutination of the bacteria, by binding of SP-A-coated particles onto the bacterial surface, and by binding of SP-A to immobilized parent K21a strain and recombinant strains that switched their capsule from K2 to K21a. In contrast, only marginal binding of SP-A to K2 parent strain (lacking this sequence) could be detected. Furthermore, binding of capsular polysaccharide of K21a to immobilized SP-A was inhibited by mannan but not by lipopolysaccharide and K2 capsular polysaccharide. SP-A-treated macrophages bound increased numbers of parent K21a strain and recombinant strains of K21a capsule type but considerably less parent K2 strain. SP-A also enhanced killing of K21a strains by macrophages. The enhanced binding of K21a by macrophages pretreated with SP-A was inhibited by mannan, suggesting that binding is mediated by the mannose receptor on macrophages. We conclude that SP-A increases phagocytosis of the Klebsiella by two mechanisms, one of which is by serving as an opsonin, which binds to the capsular polysaccharides of the bacteria and potentially to SP-A receptors on the macrophages, and the other by activating the macrophages, resulting in increased activity of the mannose receptor.
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PMID:SP-A enhances phagocytosis of Klebsiella by interaction with capsular polysaccharides and alveolar macrophages. 912 86

Tissue factor (TF), the high affinity receptor and cofactor of factor VII, is considered as the main procoagulant in stimulated monocytes and macrophages. We studied the effect of longterm culture (differentiation) on "spontaneous" and induced (LPS) expression of TF (mRNA, antigen, cell surface associated VIIa-cofactor activity) in isolated human monocytes. TF was expressed transiently in monocytes cultured on Teflon membranes (suspension monocytes, Mo-S) and on plastic dishes (adherent monocytes, Mo-A), reaching maximal levels between days 3 and 5. Increased expression of TF was accompanied by increased stable expression of macrophage specific markers (CD71, the mannose receptor, the scavenger receptor). Bacterial lipopolysaccharide (LPS) induced (additional) TF mRNA, antigen, and activity in both Mo-S and Mo-A. In Mo-S and Mo-A of days 3 to 5, the period in which there was "spontaneous" expression of TF, TF response to LPS was considerably lower. It is concluded that during monocyte-macrophage transition, TF is "spontaneously" and transiently expressed and that with respect to TF induction the responsiveness of the cells to LPS is maintained.
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PMID:Tissue factor expression during monocyte-macrophage differentiation. 924 45

Interleukin (IL)-12 is a proinflammatory cytokine that contributes to innate resistance and to the development of antigen-specific T cell responses. Among other effects, prostaglandin E2 (PGE2) inhibits the production of IL-12 by macrophages activated with lipopolysaccharide (LPS). Here we investigated the effects of PGE2 on human dendritic cells (DCs) which develop in the presence of GM-CSF and IL-4. We demonstrate that in the absence of LPS, PGE2 dose dependently stimulated the production of IL-12 by DCs. Although PGE2 alone stimulated the production of low amounts of IL-12 only, it synergized with tumor necrosis factor (TNF)-alpha to induce high levels of IL-12 production by DCs. Addition of TNF-alpha in the absence of PGE2 had no effect on IL-12 production. Conversely, in the presence of LPS, PGE2 inhibited IL-12 production by DCs in a dose-dependent manner. The combination of PGE2 and TNF-alpha efficiently silenced mannose receptor-mediated endocytosis in DCs and readily induced neo-expression of the CD83 antigen. In addition, the expression of various surface antigens such as major histocompatibility complex class I and II, adhesion, as well as costimulatory molecules was upregulated by this treatment. The effects of PGE2 on IL-12 synthesis and CD83 expression could be mimicked by dibutyryl-cAMP and forskolin, indicating that they were due to the intracellular elevation of cAMP levels. DC treated with PGE2 and TNF-alpha were most potent in stimulating allogeneic T cell proliferation. Our data demonstrate that PGE2 contributes to the maturation of human DCs and that PGE2 can be a potent enhancer of IL-12 production by human DCs.
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PMID:Prostaglandin E2 and tumor necrosis factor alpha cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production. 934 19

The innate immune system is activated by pathogens or environmental antigens following their binding by recognition molecules such as mannan-binding lectin, C-reactive protein and the mannose receptor. Natural antibody, which represents a collection of germline-encoded antigen recognition molecules, is also important in recognition of pathogens and activation of the innate immune system via the classical pathway of complement activation. The major source of natural antibody is CD5+ B-1 cells which differ from conventional B cells (B-2 cells) firstly because they are thought to require contact with antigen for expansion and maintenance and secondly because in general they do not appear to undergo somatic hypermutation. We review results which support an important role for complement in maintenance of B-1 cells, the effect being mediated by B cell expression of complement receptors CD21 and CD35. We propose that complement and natural antibody are interdependent: clonal selection and expansion of CD5+ B-1 cells is dependent on contact with antigen coated by the complement component C3d, while efficient recognition of pathogens and activation of complement is dependent in a large part on natural antibody. This hypothesis is supported by the finding that mice deficient in CD21 and CD35 have a reduced number of CD5+ B-1 cells and are missing specificities for certain antigens commonly found in wild-type mice, such as lipopolysaccharide, Escherichia coli surface antigens and neoepitopes expressed on hypoxic intestinal endothelium.
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PMID:Linkages of innate and adaptive immunity. 952 8

We studied the expression of the mannose receptor (ManR) in rat microglial cells. Microglial cells are the central nervous system resident macrophages, key participants of the innate immune response. ManR is a differentiation marker and a relevant glycoprotein for the phagocytic and endocytic function of macrophages. Because there is evidence suggesting that ManR could mediate some of the nonenzymatic effects of acetilcholinesterase (AchE) and the enzyme seems to be involved in Alzheimer's disease (AD), we looked for ManR in microglia, evaluating the functionality of the receptor. We isolated microglial cells from the brain of 2-day-old neonatal rats. Microglial cells, identified by their specific staining with the lectin Griffonia simplicifolia, expressed ManR, being detected by immunocytochemistry, Western blot, and immunoprecipitation. Microglial ManR was downregulated by lipopolysaccharide (LPS) and upregulated by dexamethasone, as described for peripheral macrophages. Microglial ManR was functional and able to internalize horseradish peroxidase (HRP), a known ManR ligand, in a mannan-inhibitable manner. The presence of a functional ManR in microglia opens the possibility that ManR could participate in multiple physiologic and pathologic conditions in the central nervous system (CNS), including inflammation, ischaemia, and neurodegenerative diseases such as AD.
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PMID:Mannose receptor is present in a functional state in rat microglial cells. 1051 12

Human monocyte-derived dendritic cells (DC) use mannose receptor (MR)-mediated endocytosis for efficient antigen capture and targeting to the endosomal/lysosomal compartment. Active biosynthesis of the MR takes place in such cells. We now report that a substantial percentage (up to 20%) of these newly synthesized MR are secreted into the culture medium. The secretion of the soluble MR (sMR) was found to be proportional to the rate of synthesis. The addition of the inflammatory mediator lipopolysaccharide (LPS) to DC, known to induce maturation, strongly reduced MR synthesis, expression and shedding of the MR. The sMR is approximately 10 kDa smaller than the membrane-bound form, but contains an intact N-terminus, indicating the lack of the cytoplasmic and transmembrane region. The sMR appeared to be directly generated from the cell-bound form, indicative of proteolytic cleavage. Importantly, the sMR has maintained its mannose-binding properties since it was capable of binding a mannosylated ligand. The high amount of sMR released by DC and its ability to bind mannosylated ligand might indicate that this molecule plays a role in the transport of mannosylated proteins from the site of inflammation to other parts of the body. Whether that contributes to the generation of immune responses remains to be determined.
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PMID:Human dendritic cells shed a functional, soluble form of the mannose receptor. 1054 81


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