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)

Injury to the vascular endothelium and the subsequent inflammatory response are considered prerequisites for the development of atherosclerosis. Platelet-derived growth factor (PDGF) production by and monocyte adhesion to aortic endothelial cells (EC) may participate in this inflammatory process and therefore are two potential targets for control by anti-inflammatory agents. Our previous studies have demonstrated that monocyte adhesion and PDGF production are stimulated by thrombin in EC. Here, we provide evidence that treatment of EC with the anti-inflammatory agent 3-deazaadenosine (c3Ado) effectively abolished thrombin-stimulated PDGF production and monocyte adhesion. c3Ado had no significant effect on either basal monocyte adhesion or constitutive PDGF production. c3Ado was also effective in negating monocyte adhesion induced by other agonists, such as interleukin-1, phorbol 12-myristate 13-acetate (PMA), and lipopolysaccharide. Northern analysis demonstrated that c3Ado significantly reduced thrombin- and PMA-stimulated steady-state levels of PDGF-A chain, PDGF-B chain, and endothelial-leukocyte adhesion molecule-1 (ELAM-1) mRNAs. Nuclear run-on studies demonstrated that a marked transcriptional activation of these genes by thrombin and PMA was abrogated by c3Ado treatment. The transcriptional rate of the alpha-tubulin gene was unaffected by the drug. Antibody binding studies with an anti-ELAM-1 monoclonal antibody 7A9 revealed that thrombin-stimulated EC expression of ELAM-1 was abolished by c3Ado, indicating that the suppression of ELAM-1 expression on EC surface may be a mechanism by which c3Ado interferes with monocyte adhesion. Experiments with the nucleoside transport inhibitor nitrobenzylthioinosine suggested that the transport of c3Ado into EC was required for its inhibitory activity. In addition, L-homocysteine thiolactone was found to potentiate the inhibitory activity of c3Ado, suggesting that the accumulation of intracellular c3Ado homocysteine may be the underlying mechanism by which c3Ado inhibits thrombin-induced EC function. Taken together, these results indicate that c3Ado may prove effective against vascular injury and inflammation through its ability to inhibit induction of both monocyte adhesion and PDGF production.
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PMID:3-Deazaadenosine inhibits thrombin-stimulated platelet-derived growth factor production and endothelial-leukocyte adhesion molecule-1-mediated monocytic cell adhesion in human aortic endothelial cells. 137 93

Several studies during recent years have demonstrated the potential for vascular smooth muscle cells (SMC) and dermal fibroblasts to participate in immune interactions such as antigen presentation and alloreactivity. The molecular interactions mediating lymphocyte adhesion to these mesenchymal cells have, however, not previously been characterized in detail. In the present study we demonstrate ICAM-1 (CD54) expression by cultured human SMC and its up-regulation by IL-1, IFN-gamma, and bacterial lipopolysaccharide. Monoclonal antibodies were used to define the molecular interactions in the adhesion of 51Cr-labelled T lymphoblasts to adherent SMC and fibroblasts. ICAM-1 appeared to mediate adhesion of T lymphocytes by binding to the beta 2-integrin CD11a/CD18 (LFA-1) expressed by the lymphoblasts. We present evidence for the involvement of at least three different mechanisms in the adhesion of activated T lymphocytes to cultured fibroblasts. It was found that beta 2-integrin-mediated interaction could only account for less than half of the binding activity. The remaining adhesion was partly mediated by beta 1-integrins, presumably via VLA-5 since an anti-VLA-5 antibody and an RGD-containing peptide blocked adhesion to the same degree. However, antibodies to beta 1-, beta 2-, and beta 3-integrin subunits added together only inhibited adhesion by approximately 50%. The residual adhesion could be blocked by inhibition of cell metabolism and was increased by stimulation of the lymphocytes with phorbol ester, suggesting involvement of other, as yet undefined, adhesion molecules. The molecular interactions between lymphocytes and mesenchymal cells demonstrated in this study may have implications in several inflammatory conditions such as vasculitis, atherosclerosis, and connective tissue diseases.
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PMID:Adhesion of activated T lymphocytes to vascular smooth muscle cells and dermal fibroblasts is mediated by beta 1- and beta 2-integrins. 138 Jan 79

The effect of LPSw (a lipopolysaccharide from wheat flour) on cholesterol catabolism was examined using WHHL (Watanabe heritable hyperlipidemic) rabbit, which is an experimental model of familial hyperlipidemia. The serum cholesterol level of the animal decreased by the addition of LPSw to drinking water. Following cessation of the addition of LPSw to the drinking water, the cholesterol level was decreased for 30 to 40d and then gradually elevated. The serum level of apolipoprotein B, which is a constituent of apolipoprotein of low density lipoprotein (LDL), also decreased in accord with serum cholesterol at a nearly coincident rate. Conversely, the level of apolipoprotein A-I, which is a constituent of apolipoprotein of high density lipoprotein (HDL), did not change, nor did HDL-cholesterol. Furthermore, the atherosclerosis risk factor, expressed as the ratio of apolipoprotein B to apolipoprotein A-I, was decreased by LPSw administration.
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PMID:Homeostasis as regulated by activated macrophage. VII. Suppression of serum cholesterol level by LPSw (a lipopolysaccharide from wheat flour) in WHHL (Watanabe heritable hyperlipidemic) rabbit. 139 46

Tissue factor (TF) which initiates clotting process can be expressed by stimulated endothelial cells (EC). TF is an apolipoprotein requiring an association with phospholipids (PL) in order to become active. Also PL constitute an important storage pool of polyunsaturated fatty acids (PUFAs) in EC which can be modulated by diet or cell medium supplementation. In order to test the effect of such manipulation upon TF activity, we have pre-enriched human EC cultures with different fatty acids of nutritional interest. TF was evaluated after 4 h of thrombin stimulation by using a chromogenic method. Without additional stimulating agents, these acids have no effect on the basal level of TF. Eicosapentaenoic and docosapentaenoic acids appeared to be ineffective at the stimulated TF level. Only adrenic acid (22:4(n-6)) has been found to significantly enhance TF activity of thrombin-stimulated endothelial cells. Other TF inducers were also tested after 22:4(n-6) enrichment. An increase tendency of TF expression was found only with tumor necrosis factor, whereas interleukin-1 beta, lipopolysaccharide and especially phorbol myristate acetate stimulations were not significantly modified. The priming effect of adrenic acid on thrombin stimulated TF expression might involve alterations of signal transduction pathways rather than modifications of apolipoprotein III environment. Adrenic acid, which is a prostacyclin inhibitor, appears to be potential prothrombotic agent.
Atherosclerosis 1992 Jul
PMID:Priming effect of adrenic acid (22:4(n-6)) on tissue factor activity expressed by thrombin-stimulated endothelial cells. 164 92

Oxidation of low density lipoprotein (LDL) leads to more rapid uptake by arterial wall macrophages and foam cell formation. Inhibiting LDL oxidation may impede these processes and offers a new mechanism to retard atherogenesis. The 21-aminosteroids, derived from methylprednisolone, are potent inhibitors of free radical production by stimulated monocytes and also are scavengers of lipid peroxyl radicals. The 21-aminosteroid, U74500A, was added to a mixture of low density lipoprotein cholesterol and human monocytes to which lipopolysaccharide was add to stimulate the monocytes. At a final concentration of 10 microM, U74500A reduced the production of lipid peroxidation from 6.10 +/- 1.11 to 0.84 +/- 0.16 nmol (mean +/- SEM) MDA equivalent/1 x 10(6) monocytes, as measured by a thiobarbituric acid reacting substance (TBARS) assay. Similarly 10 microns U74500A reduced Cu2+ induced LDL oxidation from 12.28 +/- 0.10 (in vehicle) to 0.49 +/- 0.12. These observations suggest that the 21-aminosteroids should be evaluated in animal models as a potential therapy to retard atherogenesis, especially considering their apparent lack of mineralocorticoid and glucocorticoid side-effects.
Atherosclerosis 1991 Oct
PMID:A 21-aminosteroid inhibits oxidation of human low density lipoprotein by human monocytes and copper. 175 90

Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.
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PMID:The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by human monocyte-derived macrophages. 190 87

The present study was designed to investigate the capacity of human vascular smooth muscle cells (SMCs) to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein [MCP]) and by way of comparison, a related polypeptide activator of neutrophils (known as interleukin-8 [IL-8] or neutrophil activating protein-1 [NAP-1]. On exposure to IL-1, SMCs released high levels of chemotactic activity for monocytes, which could be removed by absorption with anti-MCP antibodies. MCP production by activated SMCs was comparable to that of IL-1-stimulated umbilical vein endothelial cells. Activated SMCs released appreciable levels of IL-8, as determined by a specific enzyme-linked immunosorbent assay, but little chemotactic activity for neutrophils. IL-1-treated SMCs expressed high levels of both MCP and IL-8 mRNA transcripts, as assessed by Northern blot analysis. Tumor necrosis factor and bacterial lipopolysaccharide but not IL-6 also induced MCP and IL-8 gene expression in SMCs. Nuclear runoff analysis revealed that IL-1 augmented transcription of the MCP and IL-8 genes. The capacity of SMCs to produce a cytokine (MCP) that recruits and activates circulating mononuclear phagocytes may be of considerable importance in the pathogenesis of vascular diseases (e.g., vasculitis and atherosclerosis) that are characterized by monocyte infiltration of the vessel wall.
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PMID:Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. 191 3

Both macrophages and platelets play an important role in atherogenesis. We studied the effect of conditioned medium obtained from human monocyte-derived macrophages on in vitro platelet aggregation. Incubation of macrophage-conditioned medium (MCM) with platelets resulted in enhanced platelet aggregation (up to 35% difference between basal and MCM-stimulated activity), which was time dependent. This MCM effect on platelet function was increased both with time of mononuclear cell culturing (up to 10 days) and with the time of macrophage incubation in serum-free medium (up to 24 hours) prior to MCM collection. MCM from either cholesterol-loaded macrophages or from macrophages obtained from patients with familial hypercholesterolemia demonstrated a 37% and 20% increased effect, respectively, in comparison to MCM derived from normal subjects. Macrophage activation with lipopolysaccharide resulted in the harvesting of a MCM that enhanced platelet activity 60% more than MCM obtained from nonactivated cells. The active component of MCM was inhibited fivefold following heating at 100 degrees C for 10 minutes or after treatment with trypsin or protease, but was not affected by antioxidants. MCM activation of blood platelets may be of importance in atherogenesis. Understanding the mechanisms involved may contribute to an improved appreciation of the role of both platelets and macrophages in atherosclerosis.
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PMID:Secretory products from human monocyte-derived macrophages enhance platelet aggregation. 200 39

Probucol, 4,4'-(isopropylidenedithio)bis(2,6-di-tert-butyl-phenol), has been shown to inhibit atherogenesis in genetically hypercholesterolemic (Watanabe) rabbits. Since atherosclerotic lesions contain macrophages capable of screting interleukin 1 (IL 1) and other cytokines that could contribute to the pathogenesis of the disease, we have investigated whether probucol affects IL 1 secretion. Resident peritoneal macrophages from mice dosed with probucol secreted 40-80% less IL 1 than macrophages from control animals when stimulated in vitro with lipopolysaccharide (LPS). The inhibitory effect of probucol was observed when IL 1 was assayed by the standard bioassay, the thymocyte proliferation assay, or a competitive IL 1 receptor binding assay. Probucol treatment had no effect on LPS-induced membrane IL 1 expression; secretion of tumor necrosis factor (TNF); Con A-induced splenic interleukin 2 (IL 2) and interleukin 3 (IL 3) release; and prostaglandin- or zymosan-induced secretion of prostacyclin, leukotriene C4, acid phosphatase, or superoxide anion. In contrast to the effect of oral administration, direct addition of probucol to macrophage cultures did not inhibit IL 1 release. Probucol administration did, however, inhibit the fall in serum zinc level induced by intravenous injection of LPS in zymosan-primed mice but had no effect on the LPS-induced increase in serum triglyceride levels, which indirectly confirms that probucol administration inhibits IL 1 but not TNF secretion. Paw granuloma induced in mice by heat-killed mycobacteria was inhibited by oral administration of probucol, an effect that may be attributable to inhibition of IL 1 secretion. Probucol neither reduced zymosan-induced liver granulomata in mice nor inhibited adjuvant-induced arthritis in rats. We suggest that inhibition of IL 1 secretion from macrophages by probucol contributes to its therapeutic effects in atherosclerosis and may also result in beneficial activity in some chronic inflammatory diseases.
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PMID:Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. 231 80

Cytokines such as tumor necrosis factor alpha (TNF) profoundly affect endothelial cell function, promoting for example interaction with leukocytes and inducing a procoagulant phenotype. Changes of this nature are likely to be central to the proinflammatory effects of TNF. In order to elucidate molecular mechanisms by which TNF alters endothelial cell function we utilized differential plaque hybridization to identify TNF-responsive genes. Forty TNF-inducible cDNAs were identified which on cross-hybridization were found to arise from six unique genes. DNA sequencing of these cDNAs revealed two encoded known cytokine-induced genes, endothelial leukocyte adhesion molecule 1 and neutrophil chemotactic factor. One of the cDNAs encodes a recently described monocyte-specific chemotactic factor not previously associated with endothelium. The production of a monocyte chemotaxin by cytokine-activated endothelium has important implications for understanding the role of the vessel wall in disease states such as atherosclerosis and may also in part explain the indirect angiogenic activity of TNF. The three other cDNAs are completely novel as judged by data bank searches of partial DNA sequences and remain unidentified. On exposure of endothelial cells to TNF there is a rapid and substantial increase in levels of mRNA encoding the six genes, which are further superinduced by cycloheximide. Thus these represent primary response genes as their induction does not depend on protein synthesis. Interleukin-1 beta and lipopolysaccharide are also potent inducers. Nuclear run-on studies revealed that in most cases induction by TNF is mediated largely at the transcriptional level.
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PMID:Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. 240 43


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