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)

CD14 is a key molecule responsible for the innate host inflammatory response to microbial infection. It is able to bind a wide variety of microbial ligands and facilitate the activation of both myeloid and nonmyeloid cells. However, its specific contribution to the innate recognition of bacteria is not known. Presently there is no information on the contribution of individual CD14 residues to Escherichia coli lipopolysaccharide (LPS) binding or on the molecular basis of the interaction between CD14 and LPS from other bacteria. LPS obtained from Porphyromonas gingivalis, a bacterium associated with chronic inflammatory disease, binds CD14 and activates myeloid cells but does not facilitate the activation of nonmyeloid cells. The transfer and binding of these two LPS species to soluble CD14 recombinant globulin proteins with single point mutations was examined. Functional activity of the mutant proteins was monitored by E-selectin expression on human umbilical cord endothelial cells. The analysis identified a charge reversal mutation in a single residue, E47, that demonstrated selective binding to E. coli LPS but not to P. gingivalis LPS. E-selectin activation assays indicated that proteins with mutations at position E47 maintained their structural integrity. Other mutations, including a charge reversal mutation of residue E58, did not significantly reduce the binding of either LPS ligand or the ability of the molecule to facilitate E-selectin activation. These data demonstrate that CD14 can selectively recognize different LPS ligands.
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PMID:Identification of CD14 residues involved in specific lipopolysaccharide recognition. 897 26

Human bone marrow endothelial cells (HBMEC) are intimately involved in the homing of hematopoietic progenitor cells (HPC) to the bone marrow and in the regulation of proliferation and differentiation of these cells. Because availability of primary HBMEC and their capacity to be cultured in vitro are limited, we used isolated HBMEC to establish a cloned cell line by microinjection of a recombinant plasmid expressing simian virus 40 early genes under the control of a deletion mutant of the human vimentin promoter. Serum requirements for growth of a transformed HBMEC line (TrHBMEC) were markedly decreased compared with those of primary cells, and added growth factors were not required for proliferation. Cells took up acetylated low-density lipoprotein normally, bound to Ulex europaeus lectin, and stained positively for von Willebrand factor, P-selectin, CD31, CD34, CD44, very late antigen-5, and intercellular adhesion molecule-2 (ICAM-2). After treatment with TNF-alpha or lipopolysaccharide, TrHBMEC increased surface expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and ICAM-1 in a manner similar to primary HBMEC. In contrast, IL-1 beta elicited much less up-regulation of these adhesion molecules than in primary cells. In previous work, we reported that, in a flow adhesion model, rolling of peripheral blood CD34+ cells on primary HBMEC was E-selectin-dependent, whereas VCAM-1 and ICAM-1 contributed to firm adhesion. In the present study, we show that HPC adhere in a similar way to TrHBMEC. A less-pronounced role for VCAM-1 and ICAM-1 was found in the adhesion of HPC to human umbilical vein endothelial cells. Furthermore, significantly more CD34+ cells adhered to TNF-alpha-stimulated HBMEC and TrHBMEC than to similarly stimulated human umbilical vein endothelial cells. These data emphasize the importance of using microvessel HBMEC for studying the homing of HPC to the bone marrow, and indicate the usefulness of the above-described bone marrow endothelial cell line.
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PMID:Characterization of a newly established human bone marrow endothelial cell line: distinct adhesive properties for hematopoietic progenitors compared with human umbilical vein endothelial cells. 901 Apr 47

E-Selectin is an inducible, endothelium-specific, cell surface adhesion molecule that mediates inflammatory responses in the vasculature. Nonendothelial cell types such as cultured human aortic smooth muscle cells (HASMCs) lack the ability to express E-selectin. We tested the hypothesis that HASMCs express a negative regulatory factor that inhibits E-selectin gene expression. E-Selectin mRNA and gene transcription were not detected in HASMCs after treatment with tumor necrosis factor-alpha (TNF-alpha) by Northern and nuclear runoff analyses, respectively. However, both E-selectin mRNA and gene transcription were dramatically induced by TNF-alpha in the same cells pretreated with the protein synthesis inhibitor cycloheximide. Lipopolysaccharide demonstrated similar effects. Furthermore, E-selectin was detected on the cell surface of HASMCs after washing out of cycloheximide. Cycloheximide pretreatment enabled immortalized human dermal microvascular endothelial cells that have lost the ability to express E-selectin to induce both E-selectin mRNA and gene transcription in response to TNF-alpha. Induction of E-selectin mRNA by lipopolysaccharide or TNF-alpha in cycloheximide-treated HASMCs was inhibited by the antioxidant pyrrolidinedithiocarbamate and the serine protease inhibitor N alpha-L-tosyl-L-phenylalanine chloromethyl ketone, suggesting that a nuclear factor-kappa B-like mechanism may play an important role in E-selectin gene expression in HASMCs. These data strongly suggest that a labile repressor protein(s) plays an important role in inhibiting E-selectin gene expression in HASMCs likely at the level of gene transcription. Except for this repressor, HASMCs and endothelial cells may share similar regulatory mechanisms for controlling E-selectin expression.
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PMID:E-selectin gene expression in vascular smooth muscle cells. Evidence for a tissue-specific repressor protein. 904 49

A reconstituted high density lipoprotein (rHDL) containing human apolipoprotein A-I and phosphatidylcholine was tested for its ability to modify polymorphonuclear leukocyte (PMN) adherence to endothelial cells (EC) in vitro. EC stimulation for 4 h with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF alpha) resulted in a four- to sixfold increase in PMN adherence. Concomitant stimulation of EC with LPS and rHDL virtually prevented the LPS-stimulated increase in PMN adherence. Changes in adherence were paralleled by alterations in adhesion molecule expression of EC. Concomitant EC stimulation with LPS and rHDL resulted in complete inhibition of the LPS-stimulated increase in expression of E-selectin and intercellular adhesion molecule 1 (ICAM-1). In contrast, rHDL reduced the TNF alpha-induced expression of adhesion molecules as well as the PMN adherence to TNF alpha-stimulated EC by approximately 10%. The CD11/CD18-mediated PMN adherence to EC as a consequence of PMN stimulation with calcium ionophore (A23187) was diminished in the presence of rHDL after 7 min incubation by 36.1 +/- 11.4% and after 15 min incubation by 45.1 +/- 7.4%. In addition, the A23187-stimulated increase in PMN adherence to fibrinogen-coated surfaces, mediated by CD11b/CD18, was virtually eliminated in the presence of rHDL and HDL, but not in the presence of apolipoprotein A-I or natural low density lipoprotein. FACS analysis showed that PMN treated with rHDL and subsequently washed were resistant to FMLP-induced CD11b/ CD18 up-regulation. In conclusion, these data indicate that rHDL decreases cell adhesion via two mechanisms: blocking LPS activity and modifying CD11b/CD18 up-regulation on PMN.
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PMID:Reconstituted high density lipoprotein modulates adherence of polymorphonuclear leukocytes to human endothelial cells. 906 82

Bacterial pathogenesis requires proteins that sense host microenvironments and respond by regulating virulence gene transcription. For Salmonellae, one such regulatory system is PhoP-PhoQ, which regulates genes required for intracellular survival and resistance to cationic peptides. Analysis by mass spectrometry revealed that Salmonella typhimurium PhoP-PhoQ regulated structural modifications of lipid A, the host signaling portion of lipopolysaccharide (LPS), by the addition of aminoarabinose and 2-hydroxymyristate. Structurally modified lipid A altered LPS-mediated expression of the adhesion molecule E-selectin by endothelial cells and tumor necrosis factor-alpha expression by adherent monocytes. Thus, altered responses to environmentally induced lipid A structural modifications may represent a mechanism for bacteria to gain advantage within host tissues.
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PMID:Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. 909 73

Leukocyte adherence to the endothelium is an essential component of the inflammatory response during rickettsial infection. In vitro, Rickettsia conorii infection of endothelial cells enhances the expression of adhesive molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in a time- and dose-dependent manner. Rickettsial lipopolysaccharide does not seem to be involved, because polymyxin B does not reduce their expression. The intracellular presence of the organism and de novo host protein synthesis are required for expression of cell adhesive molecules, since rickettsial inactivation by formol and pretreatment of cells with cycloheximide inhibits an increase in expression. The contribution of interleukin-1alpha (IL-1alpha) to this endothelial adhesive phenotype was shown by inhibitory experiments 8 and 24 h after infection with IL-1 receptor antagonist and IL-1alpha blocking antibodies. Enhanced adherence of mononuclear cells to infected endothelial cells involved VCAM-1- and ICAM-1-dependent mechanisms at the late phase of the inflammatory response. This endothelial adhesive phenotype may constitute a key pathophysiologic mechanism in R. conorii-induced vascular injury.
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PMID:Rickettsia conorii infection enhances vascular cell adhesion molecule-1- and intercellular adhesion molecule-1-dependent mononuclear cell adherence to endothelial cells. 912 78

To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 +/- 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-alpha2-antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-alpha1-antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P > .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.
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PMID:Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. 916 Jun 78

The endothelium plays a key role in inflammation, hemostasis and organ rejection. We report here that a synthetic polyunsaturated fatty acid, 5,8,11,14-eicosatetraynoic acid (ETYA), selectively inhibits the up-regulation of several genes on endothelial cells. ETYA suppresses endothelial cell activation by inhibiting the up-regulation of adhesion molecules like E-selectin. A runoff assay for E-selectin demonstrated that the suppression is at the level of transcription. The fact that ETYA inhibits E-selectin upon stimulation with a diverse group of stimuli like lipopolysaccharide, tumor necrosis factor-alpha or phorbol 12-myristate 13-acetate, suggests that ETYA does not exert its effect by modifying membrane-bound receptors. The messenger RNA for interleukin-8 and glyceraldehyde phosphate dehydrogenase are not affected. Pre-treatment of endothelial cells with ETYA also prevents the adherence of monocytes to tumor necrosis factor-alpha-stimulated cells.
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PMID:The effect of 5,8,11,14-eicosatetraynoic acid on endothelial cell gene expression. 916 68

A two-step paradigm for leukocyte recruitment has been established in a number of tissues including the mesentery, skin, and muscle, and necessitates an initial rolling step via the selectins before firm leukocyte adhesion via the integrins. In view of the many inflammatory diseases that involve the liver, we investigated the importance of rolling and the selectins in the hepatic microvasculature and compared the responses to that of the commonly used mesentery or cremaster microvasculature. We visualized the liver microvasculature using intravital microscopy and we determined that within the liver the majority of leukocytes adhere within the sinusoids (80%) in response to a chemotactic stimulus such as FMLP (20% in postsinusoidal venules) whereas leukocytes adhere exclusively within postcapillary venules in tissue like the mouse cremaster. In the sinusoids, the adhesive response to FMLP is not dependent upon selectins inasmuch as adhesion was not reduced in the sinusoidal vessels of P-selectin-deficient mice or E-selectin/P-selectin- deficient animals in the presence or absence of L-selectin antibody. No rolling or adhesion was detected in response to FMLP in the selectin-deficient cremaster microvasculature. Immunoneutralization of selectins with fucoidan in wildtype mice eliminated rolling and adhesion in the cremaster but failed to affect adhesion in the liver sinusoids in response to FMLP. More long-term leukocyte recruitment with lipopolysaccharide (4 h) was also impaired in the cremaster but not the liver microvasculature in selectin-deficient animals. Leukocyte adhesion in the sinusoids was reduced in P-selectin-deficient mice also lacking intercellular adhesion molecule-1 (ICAM-1). This study for the first time demonstrates that selectins are not an essential step for leukocyte recruitment into the inflamed liver microvasculature.
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PMID:A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. 916 9

We have examined the effects of N-acetyl-L-cysteine (NAC), a well-characterized, thiol-containing antioxidant, on agonist-induced monocytic cell adhesion to endothelial cells (EC). NAC inhibited interleukin-1 (IL-1 beta)-induced, but not basal, adhesion with 50% inhibition at approximately 20 mM. Monocytic cell adhesion to EC in response to tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA) was similarly inhibited by NAC. Unlike published studies with pyrrolidinedithiocarbamate, which specifically inhibited vascular cell adhesion molecule 1 (VCAM-1), NAC inhibited IL-1 beta-induced mRNA and cell surface expression of both E-selectin and VCAM-1. NAC had no effect on the half-life of E-selectin or VCAM-1 mRNA. Although NAC reduced nuclear factor-kappa B (NF-kappa B) activation in EC as measured by gel-shift assays using an oligonucleotide probe corresponding to the consensus NF-kappa B binding sites of the VCAM-1 gene (VCAM-NF-kappa B), the antioxidant had no appreciable effect when an oligomer corresponding to the consensus NF-kappa B binding site of the E-selectin gene (E-selectin-NF-kappa B) was used. Because NF-kappa B has been reported to be redox sensitive, we studied the effects of NAC on the EC redox environment. NAC caused an expected dramatic increase in the reduced glutathione (GSH) levels in EC. In vitro studies demonstrated that whereas the binding affinity of NF-kappa B to the VCAM-NF-kappa B oligomer peaked at a GSH-to-oxidized glutathione (GSSG) ratio of approximately 200 and decreased at higher ratios, the binding to the E-selectin-NF-kappa B oligomer appeared relatively unaffected even at ratios > 400, i.e., those achieved in EC treated with 40 mM NAC. These results suggest that NF-kappa B binding to its consensus sequences in the VCAM-1 and E-selectin gene exhibits marked differences in redox sensitivity, allowing for differential gene expression regulated by the same transcription factor. Our data also demonstrate that NAC increases the GSH-to-GSSG ratio within the EC suggesting one possible mechanism through which this antioxidant inhibits agonist-induced monocyte adhesion to EC.
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PMID:Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced E-selectin and VCAM-1 expression. 927 99


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