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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological response to endotoxin (lipopolysaccharide (LPS)) can be regulated by two closely related LPS-binding proteins, LPS-binding protein (LBP), which potentiates LPS' inflammatory activity via interaction with the monocytic antigen CD14, and bactericidal/permeability-increasing protein (BPI), which neutralizes LPS. Both proteins bind LPS with high affinity sites in their N-terminal domains, whereas interaction between LBP and CD14 is dependent upon the LBP C-terminal domain. We have created fusions of the N- and C-terminal domains from each protein and compared the functional activities and pharmacokinetics of these fusions, the individual N-terminal domains, and the parent proteins. The N-terminal domains of BPI and LBP bound lipid A with their characteristic apparent affinity constants, regardless of the C-terminal fusion partner. In addition, the C-terminal domain of LBP allowed transfer of LPS to CD14 in conjunction with either N-terminal LPS binding domain. Proteins containing a BPI N-terminal domain had greater heparin binding capacities in vitro and were cleared more rapidly from the plasma of whole animals. Taken together, these data better define how closely related proteins such as BPI and LBP can have opposing effects on the body's response to LPS.
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PMID:Biochemical characterization of recombinant fusions of lipopolysaccharide binding protein and bactericidal/permeability-increasing protein. Implications in biological activity. 899 16

To evaluate the effect of soluble CD14 (sCD14) on human neutrophil response to lipopolysaccharide (LPS), we developed an LPS-priming assay that measures the chemiluminescence response to N-formyl-methionyl-leucyl-phenylalanine stimulation. Priming by 1 ng/mL rough LPS occurred in the presence of either serum or recombinant LPS-binding protein (LBP) only. Priming was completely CD14-dependent because preincubation of the neutrophils with an anti-CD14 monoclonal antibody prevented priming. We hypothesize that sCD14 enhances LPS response in neutrophils, but this response is not as effective as LPS response via membrane CD14 (mCD14). In our experiments sCD14 is present in an excess compared with mCD14. Priming of neutrophils occurs with low LBP, supposedly via sCD14-LPS complexes. With high LBP, addition of sCD14 inhibited LPS-priming of neutrophils. In that case, LPS may be transported to sCD14, preventing a more effective response via mCD14. In this study we demonstrate that the effect of sCD14 on neutrophil response to LPS is a delicate balance between activation and inhibition depending on concentration of serum or LBP.
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PMID:Dual effects of soluble CD14 on LPS priming of neutrophils. 902 23

The host response to the presence of lipopolysaccharide (LPS) is complex and varied. Two closely related endogenous serum proteins, LPS-binding protein (LBP) and bactericidal/permeability-increasing factor (BPI), regulate delivery of LPS to CD14 antigen on effector cell surfaces and modulate the host response to LPS. In the study presented here, plasma levels of LBP and BPI were measured, predialysis, 15 min into dialysis and postdialysis in patients dialyzed with cellulose, cellulose-tri-acetate (CTA), and polysulfone dialyzers. Further, the association between LBP levels and BPI release during hemodialysis and clinical and laboratory characteristics of patients, complement activation represented by plasma C3a levels, and monocyte cytokine production represented by interleukin-1 receptor antagonist (IL-1Ra) synthesis was also studied. Predialysis plasma levels of LBP were 14,459 +/- 544, 13,889 +/- 1362 and 12,622 +/- 6305 ng/mL, respectively, with cellulose, CTA, and polysulfone dialyzers, and postdialysis levels were 17,834 +/- 861, 20,979 +/- 8485 and 18,177 +/- 1656 ng/mL, respectively. Postdialysis plasma levels of LBP were consistently higher than predialysis levels with all three dialyzers (P < 0.05). However, plasma LBP levels were not significantly different between the three dialyzers either predialysis (P = 0.28) or postdialysis (P = 2.8). There were no significant differences in predialysis BPI levels between the three dialyzers (P = 0.21). BPI levels at 15 min of dialysis with CTA (10.91 +/- 3.65 ng/mL) and polysulfone (10.73 +/- 2.24 ng/mL) dialyzers were significantly greater (P < 0.05) than that observed with cellulose (5.49 +/- 0.66 ng/mL). Similarly, postdialysis levels with CTA and polysulfone were significantly greater (P < 0.05) than that observed with cellulose dialyzers. The percentage change in BPI levels between predialysis and 15 min was 1341 +/- 243%, 2935 +/- 1033%, and 3790 +/- 1151% for cellulose, CTA, and polysulfone dialyzers, respectively. The changes in BPI levels from predialysis to 15 min and between pre- and postdialysis samples were statistically significant for all three dialyzers (P < 0.05). Postdialysis LBP:BPI ratios were 50 +/- 6%, 18 +/- 4%, and 22 +/- 6% of predialysis ratios for cellulose, CTA, and polysulfone dialyzers, respectively. These changes were statistically significant (P < 0.05) for all three dialyzers. There was no significant correlation between baseline clinical or laboratory characteristics and predialysis LBP levels. Similarly, the correlation between BPI levels at 15 min of dialysis with the clinical and laboratory characteristics was also poor, with the exception of serum albumin (r = 0.43, P = 0.008). The correlation between BPI levels at 15 min of dialysis with plasma LBP levels (r = -0.29; P = 0.08), plasma C3a levels (r = -0.1; P = 0.55), peripheral blood mononuclear cells (PBMC) content of IL-1Ra (r = 0.01; P = 0.94), and IL-1Ra production by unstimulated (r = 0.13; P = 0.45), and endotoxin-stimulated PBMC (r = 0.32; P = 0.06) was not statistically significant. The results of this study demonstrate that dialysis with cellulose, CTA, and polysulfone dialyzers results in a significant increase in LBP and BPI levels. BPI release is probably mediated by non-complement factors and may be related to the nutritional status of the patient. The release of BPI during HD and consequent lowering of the LBP:BPI ratio could potentially afford some protection against endotoxin in the dialysate.
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PMID:Lipopolysaccharide-binding protein and bactericidal/permeability-increasing factor during hemodialysis: clinical determinants and role of different membranes. 907 15

The transcription factor Sp1 plays a crucial role in the monocyte-specific expression of CD14, a binding site (or putative receptor) for lipopolysaccharide (LPS) complexes with LPS-binding protein (LBP). By using RAW 264.7 macrophages treated with spectrally pure deep-rough-chemotype hexa-acyl LPS from Escherichia coli D31m4, three inhibitors were found to block the binding activity of transcription factor Sp1, as measured by electrophoretic mobility shift assays. These inhibitors were diphosphoryl lipid A from Rhodobacter sphaeroides (10 microg/ml); the isoquinoline-sulfonamide H-8 (10 and 100 microM), which is thought to be a cGMP-dependent protein kinase inhibitor; and the anti-inflammatory agent dexamethasone (10 microM).
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PMID:Inhibition of lipopolysaccharide-induced transcription factor Sp1 binding by spectrally pure diphosphoryl lipid A from Rhodobacter sphaeroides, protein kinase inhibitor H-8, and dexamethasone. 912 41

We used rough lipopolysaccharide (ReLPS) to construct a fluorescein-labeled LPS (FITC-LPS) with a very high labeling efficiency that bound to isolated human monocytes in a CD14-dependent fashion and that in this respect behaved indistinctively from native LPS. The CD14-dependent binding could be inhibited either by a 1,000-fold excess of unlabeled LPS or by polymyxin B, bactericidal/permeability-increasing protein, cationic protein 18, or soluble CD14. Although this FITC-LPS preparation no longer possessed the ability to prime neutrophils for the production of reactive oxygen species or to stimulate human monocytes to produce tumor necrosis factor, activation of the Limulus amoebocyte lysate cascade was comparable to activation by native LPS. Binding to monocytes was enhanced by human pooled serum (HPS) or LPS-binding protein (LBP) for LPS concentrations up to 100 ng/ml and was completely CD14 dependent. For LPS concentrations exceeding 100 ng/ml, binding was still partially CD14 dependent, but not HPS or LBP dependent. CD14-dependent association of LPS with monocytes was shown to be totally saturable. In conclusion, we found an HPS- or LBP-dependent binding of FITC-LPS to monocytes that was CD14 dependent at up to 100 ng of LPS per ml, and saturation of binding was shown.
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PMID:Saturable CD14-dependent binding of fluorescein-labeled lipopolysaccharide to human monocytes. 916 63

An early event in septic shock is the activation of macrophages by a complex consisting of lipopolysaccharide (LPS), LPS-binding protein (LBP), and the cell surface antigen CD14. The complexes that form between [3H]ReLPS (ReLPS is deep-rough-chemotype hexacyl LPS from E. coli D31m4), soluble CD14 (sCD14), and LBP were analyzed by two independent methods, native (nondenaturing) gel electrophoresis and size-exclusion high-performance liquid chromatography (HPLC). This is the first reported use of HPLC to purify and study LPS-protein complexes. The binding of [3H]ReLPS to LBP and sCD14 was inhibited by preincubation with diphosphoryl lipid A from Rhodobacter sphaeroides (RsDPLA), a potent LPS antagonist. In addition, [3H]ReLPS bound to LBP and to a truncated form of sCD14 [sCD14(1-152)] that contained the LPS binding domain. Binding to both proteins was blocked by RsDPLA. Thus, RsDPLA competes in a 1:1 ratio for the same or nearby binding sites on ReLPS complexes. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of aggregated ReLPS eluting from the HPLC indicated that only LBP, not sCD14, was bound to the aggregated ReLPS. This finding supports the binary model of LPS complex formation with LBP and sCD14.
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PMID:Diphosphoryl lipid A from Rhodobacter sphaeroides inhibits complexes that form in vitro between lipopolysaccharide (LPS)-binding protein, soluble CD14, and spectrally pure LPS. 923 47

The stimulation of nonmyeloid cells by lipopolysaccharide (LPS) is mediated by the serum protein, soluble CD14 (sCD14). We have examined the interaction of sCD14 with whole cells using a biologically active radiolabeled sCD14 molecule as a ligand. Specific binding of sCD14 to nonmyeloid cells is detected only when it is first incubated with both LPS and the serum LPS-binding protein (LBP). Through the use of an anti-CD14 monoclonal antibody, we demonstrate that sCD14 must interact with LPS in order for cellular binding to occur. Although LBP is traditionally known to function as a catalyst in the transfer of LPS to sCD14, our results reveal that LBP is actually a physical part of sCD14-containing, cell-associating complexes. The LPS- and LBP-dependent cell surface binding of sCD14 appears to be distinct from events leading to cell stimulation, since certain anti-CD14 and anti-LBP monoclonal antibodies have different effects on cellular binding versus cellular activation. Bound sCD14 is internalized, indicating that the LBP- and LPS-dependent binding of sCD14 may represent a novel general mechanism by which nonmyeloid cells clear LPS.
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PMID:Cellular binding of soluble CD14 requires lipopolysaccharide (LPS) and LPS-binding protein. 928 19

The activation of leukocytes by bacterial cell wall lipopolysaccharide (LPS) contributes to the pathogenesis of septic shock. It is well established that, in the presence of plasma LPS-binding protein (LBP), LPS binds with high affinity to CD14. The binding of LPS to CD14 has been associated with the activation of cells, although available evidence indicates that CD14 itself does not transduce intracellular signalling. The physiological function of this interaction is to promote host defense mechanisms of cells to combat the infection and clear LPS from the circulation. At higher concentrations of LPS, however, the activation of cells can take place in the absence of LBP and CD14, presumably through a distinct low-affinity signalling LPS receptor. On the evidence published by us and others, we propose that in neutrophils, and possibly other leukocytes, L-selectin can act as a low-affinity LPS receptor.
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PMID:L-selectin: a novel receptor for lipopolysaccharide and its potential role in bacterial sepsis. 936 86

The host response to Gram-negative bacterial infection is influenced by two homologous lipopolysaccharide (LPS)-interactive proteins, LPS-binding protein (LBP) and the bacteridical/permeability-increasing protein (BPI). Both proteins bind LPS via their N-terminal domains but produce profoundly different effects: BPI and a bioactive N-terminal fragment BPI-21 exert a selective and potent antibacterial effect upon Gram-negative bacteria and suppress LPS bioactivity whereas LBP is not toxic toward Gram-negative bacteria and potentiates LPS bioactivity. The latter effect of LBP requires the C-terminal domain for delivery of LPS to CD14, so we postulated that the C-terminal region of BPI may serve a similar delivery function but to distinct targets. LBP, holoBPI, BPI-21, and LBP/BPI chimeras were compared for their ability to promote uptake by human phagocytes of an encapsulated, phagocytosis-resistant strain of Escherichia coli. We show that only bacteria preincubated with holoBPI are ingested by neutrophils and monocytes. These findings suggest that, when extracellular holoBPI is bound via its N-terminal domain to Gram-negative bacteria, the C-terminal domain promotes bacterial attachment to neutrophils and monocytes, leading to phagocytosis. Therefore, analogous to the role of the C-terminal domain of LBP in delivery of LPS to CD14, the C-terminal domain of BPI may fulfill a similar function in BPI-specific disposal pathways for Gram-negative bacteria.
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PMID:An opsonic function of the neutrophil bactericidal/permeability-increasing protein depends on both its N- and C-terminal domains. 938 Jul 44

Gram-negative bacterial lipopolysaccharide (LPS) stimulates phagocytic leukocytes by interacting with the cell surface protein CD14. Cellular responses to LPS are markedly potentiated by the LPS-binding protein (LBP), a lipid-transfer protein that binds LPS aggregates and transfers LPS monomers to CD14. LBP also transfers LPS to lipoproteins, thereby promoting the neutralization of LPS. LBP present in normal plasma has been shown to enhance the LPS responsiveness of cells in vitro. The role of LBP in promoting LPS responsiveness in vivo was tested in LBP-deficient mice produced by gene targeting in embryonic stem cells. Whole blood from LBP-deficient animals was 1,000-fold less responsive to LPS as assessed by the release of tumor necrosis factor (TNF)-alpha. Blood from gene-targeted mice was devoid of immunoreactive LBP, essentially incapable of transferring LPS to CD14 in vitro, and failed to support cellular responses to LPS. These activities were restored by the addition of exogenous recombinant murine LBP to the plasma. Despite these striking in vitro findings, no significant differences in TNF-alpha levels were observed in plasma from wild-type and LBP-deficient mice injected with LPS. These data suggest the presence of an LBP-independent mechanism for responding to LPS. These LBP knockout mice may provide a tool for discovering the nature of the presumed second mechanism for transferring LPS to responsive cells.
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PMID:Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to profound suppression of LPS responses ex vivo, whereas in vivo responses remain intact. 939 75


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