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)

Human serum and low density lipoproteins (LDLs) were shown to inactivate endotoxin (lipopolysaccharide [LPS]) by testing the effect of LPS interactions with serum or LDL on the activation of human monocytes. Sera and LDL preparations from four patients with familial hypercholesterolemia were used to demonstrate the inhibition of LPS from inducing interleukin-1 release. Before LDL removal by immunoapheresis, the patients' sera were able to inactive approximately fivefold more LPS than after LDL removal. The LPS-inactivating capacity lost during apheresis could essentially be retrieved in the LDL-rich eluate from the immunoadsorption columns. Because patients were treated frequently with immunoapheresis, their LDL levels before LDL removal were not markedly elevated. These patients' sera before LDL removal were shown to inactivate amounts of LPS comparable to those inactivated by the sera from three healthy volunteers. LDL prepared by ultracentrifugation showed similar LPS inactivation as LDL prepared by immunoapheresis. We conclude that the inhibition of LPS-induced monocyte activation by human serum is dependent to a large extent on the LDL fraction. LDLs were demonstrated to inhibit LPS from inducing interleukin-1 release by human monocytes.
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PMID:Low density lipoproteins inhibit endotoxin activation of monocytes. 154 93

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

Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the in vitro ability of platelets to aggregate and of monocytes to express procoagulant (tissue factor) activity (PCA) were evaluated in five patients who are homozygous for familial hypercholesterolemia (FH) before and after a single and a regular 5-month cholesterol removal by low density lipoprotein (LDL) apheresis. The biweekly procedure resulted in a 25% to 30% reduction (approximately 150 mg/dl) in total and LDL cholesterol (both were greater than 550 mg/dl at the beginning of the study). The basal levels of t-PA antigen and fibrinolytic activity before and after 10 minutes of venous stasis, basal PAI activity, and PAI-1 antigen were comparable to controls and were not affected by LDL apheresis. Likewise, regardless of the cholesterol removal, the PCA of freshly isolated monocytes and that of monocytes incubated with lipopolysaccharide did not differ from control values. Finally, the pre-apheresis sensitivity of platelets to adenosine diphosphate, arachidonic acid, and collagen was 1.5 to 2 times the normal value. This ratio was unchanged throughout the 5-month procedure. We conclude that fibrinolysis and monocyte PCA are normal in FH patients, whereas platelet aggregation is abnormally high, and none of these parameters is significantly affected by a 25% to 30% reduction in total and LDL cholesterol by LDL apheresis. Furthermore, our data suggest that removal of cholesterol from plasma by LDL apheresis is important for gaining insight into the mechanisms involved in the ischemic complications of arteriosclerosis in FH patients.
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PMID:Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis. 212 91

Cells of the arterial wall including macrophages were shown to oxidize low density lipoprotein (LDL) in vitro. Upon incubation of LDL with J-774.A1 macrophage-like cell line for 18 h in the presence of 1 microM CuSO4, extensive macrophage-mediated oxidation of the LDL fatty acids and cholesterol moieties was demonstrated. Similar results were found with mouse peritoneal macrophages or human monocyte-derived macrophages. Several lines of evidence suggest that LDL binding to the LDL receptor on macrophages is required for the cell-mediated oxidation of LDL. 1) Incubation of the cells in the presence of monoclonal antibody to the LDL receptor (IgG-C7), substantially inhibited lipoprotein oxidation. 2) Pretreatment of LDL with monoclonal antibodies to the LDL receptor binding domains on the LDL apoB-100 (mAbs B1B6 and B1B3) inhibited cell-mediated oxidation of LDL by 52-95%. 3) Down-regulation of the macrophage LDL receptors (by preloading the cells with cholesterol) reduced LDL oxidation by 42%. 4) Up-regulation of the LDL receptor (by macrophage incubation in serum-free medium) was associated with 80% elevation in LDL oxidation. 5) Macrophage activation with lipopolysaccharide up-regulated the LDL receptors and was associated with up twofold increase LDL oxidation. 6) Human monocyte-derived macrophages from a patient with homozygous familial hypercholesterolemia, which lack the LDL receptor, failed to oxidize the LDL. 7) On using acetylated LDL or methylated LDL, which do not bind to the LDL receptor, macrophage-mediated oxidation of the lipoprotein did not occur. The binding of LDL to the macrophage LDL receptor under oxidative stress induced the oxidation of extracellular unbound LDL as demonstrated by cell-mediated lipid peroxidation of mAb B1B6-treated LDL by cells that were preincubated with native LDL. Furthermore, macrophage conditioned medium (MCM) that was obtained after 5 h of cells preincubation with native LDL under oxidative stress (1 microM CuSO4), followed by lipoprotein removal and a further 18 h of cell incubation (but not MCM that was similarly obtained without cell preincubation with LDL), was found to contain oxidized linoleic and arachidonic acids and was able to induce LDL lipids peroxidation. In conclusion, macrophage-mediated oxidation of LDL requires an initial binding of the lipoprotein to the LDL receptor on the cell surface under oxidative stress. This interaction leads to the formation and release of cellular oxidized polyunsaturated fatty acids that can oxidize the LDL molecule extracellularly.
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PMID:Macrophage-mediated oxidation of extracellular low density lipoprotein requires an initial binding of the lipoprotein to its receptor. 801 75

Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-stimulated production of pro-inflammatory cytokines. We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR-/-). The LDLR-/- mice challenged with LPS had an eightfold increased LD50 when compared with the wild type controls (C57Bl/6J), while tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1 alpha) plasma concentrations were decreased twofold. LDLR-/- mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae. No differences in the outgrowth of bacteria in the organs were present between the two groups, while circulating cytokine concentrations were decreased twofold in LDLR-/- mice. In contrast, the LPS-stimulated in vitro production of cytokines by peritoneal macrophages of LDLR-/- mice was significantly increased compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR-/- mice. In conclusion, endogenous LDL can protect against the lethal effects of endotoxin and Gram-negative infection. At least part of this protection is achieved through decreased in vivo production of pro-inflammatory cytokines, in spite of increased cytokine production capacity.
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PMID:Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. 861 67

Low-density lipoprotein (LDL)-receptor deficient mice, thus hypercholesterolemic, combine protection against infection with an ex vivo two- to threefold higher pro-inflammatory cytokine production in macrophages. A pro-inflammatory cytokine profile ex-vivo is also associated with survival of gram-negative sepsis in man. We hypothesized that high lipoprotein levels would be associated with a pro-inflammatory cytokine production and could explain the resistance to fatal infection. We treated 10 patients with familial hypercholesterolemia (FH) with HMG-CoA reductase inhibitors, and 13 patients with endogenous hypertriglyceridemia (HTG) with fibrates. Blood samples were stimulated ex vivo with lipopolysaccharide (LPS), to assess the cytokine production capacity. FH patients had significantly lower tumor necrosis factor-alpha (TNF-alpha) production, compared to normolipidemic controls (P=0. 001). Lipid lowering treatment in FH patients did not affect TNF-alpha production. HTG patients showed significantly higher TNF-alpha production at baseline than matched normolipidemic controls (P<0.001), while lowering of serum triglycerides in these patients resulted in a significant decrease in TNF-alpha production (P=0.019). The IL-10 production was not affected. These data refute our hypothesis that high LDL-cholesterol levels are associated with a pro-inflammatory cytokine production capacity. In contrast, the study suggests that very-low-density lipoprotein (VLDL) in hypertriglyceridemic patients augments TNF-alpha production.
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PMID:Hyperlipoproteinemia affects cytokine production in whole blood samples ex vivo. The influence of lipid-lowering therapy. 1065 78

Targeted gene disruption or overexpression of 12/15-lipoxygenase in mice on the genetic background of apolipoprotein E or low density lipoprotein-receptor (LDL-R) deficiency has implicated 12/15-lipoxygenase in atherogenesis. The data support indirectly a role for 12/15-lipoxygenase in the oxidative modification of low density lipoprotein. In this study we set out to explore other potential mechanisms for 12/15-lipoxygenase in atherosclerosis using apolipoprotein B mRNA editing catalytic polypeptide-1/LDL-R double-deficient mice, a model highly related to the human condition of familial hypercholesterolemia. 12/15-Lipoxygenase deficiency in this strain led to approximately 50% decrease in aortic lesions in male and female mice at 8 months on a chow diet in the absence of cholesterol differences. While studying 12/15-lipoxygenase-deficient macrophages in culture, we discovered a remarkable selective defect (75-90% decrease) in interleukin-12 production but not in tumor necrosis factor-alpha or nitric oxide release, in response to lipopolysaccharide in the presence or absence of interferon-gamma priming. The lipopolysaccharide/interferon-gamma response was associated with a 33-50% decrease in nuclear interferon consensus sequence-binding protein, which is consistent with interferon consensus sequence-binding protein containing protein complex-dependent regulation of the interleukin-12 p40 gene. The decrease in interleukin-12 production was recapitulated in vivo in mouse aortas of the triple knockout group and was reflected in a marked decrease in interferon-gamma expression. The data provide support for a novel mechanism linking the 12/15-lipoxygenase pathway to a known immunomodulatory Th1 cytokine in atherogenesis.
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PMID:Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. 1212 8

We examined the role of lipoprotein receptors in mediating chylomicron-bound lipopolysaccharide (CM-LPS)-induced cytokine tolerance in rodent hepatocytes. We found that 2 h of pretreatment with CM-LPS (5 mg TG/mL) was sufficient to induce cytokine tolerance, as measured by decreased nitric oxide (NO) production by hepatocytes (20% of the Control group, P < 0.03). Tolerance was evident as early as 2 h after pretreatment and disappeared after 40 h. Furthermore, we evaluated the roles of the low-density lipoprotein (LDL) receptor (LDLR) and LDL receptor-related protein (LRP) in the induction of cytokine tolerance in hepatocytes. Biochemical inhibition of the receptors or use of hepatocytes from LDLR-deficient mice revealed that functional LDLR was necessary for the induction of tolerance. However, by increasing the pretreatment time, the LRP compensated for the absence of the LDLR in induction of cytokine tolerance. In conclusion, CM-LPS-mediated induction of cytokine tolerance to proinflammatory cytokines is a time- and dose-dependent process that requires functional lipoprotein receptors. These findings underscore an interrelationship between TG-rich lipoprotein metabolism and innate immunity.
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PMID:Induction of cytokine tolerance in rodent hepatocytes by chylomicron-bound LPS is low-density lipoprotein receptor dependent. 1257 25

To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-alpha-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC50 values = 6, 10, and 25 microM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.
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PMID:AGI-1067: a multifunctional phenolic antioxidant, lipid modulator, anti-inflammatory and antiatherosclerotic agent. 1262 63

We demonstrated previously that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) and, specifically, the component lipid 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphorylcholine increase interleukin-8 (IL-8) synthesis in aortic endothelial cells. The goal of the current studies was to characterize the receptor complex mediating the increased transcription of IL-8. We demonstrate that scavenger receptor class A, types I and II, lectin-like ox-LDL receptor-1, macrophage receptor with collagenous structure, and CD36 are not responsible for the increase in IL-8. Using dominant-negative constructs and antisense oligonucleotides, we demonstrate a role for Toll-like receptor 4 (TLR4) as the ox-PAPC receptor mediating IL-8 transcription. We demonstrate that a glycosylphosphatidylinositol (GPI)-anchored protein is also necessary because phosphatidylinositol-specific phospholipase C pretreatment inhibited the effect of ox-PAPC. CD14, a GPI-anchored protein that associates with TLR4 in mediating lipopolysaccharide action, did not appear to mediate ox-PAPC action because ox-PAPC-induced IL-8 transcription was not blocked by anti-CD14 neutralizing antibodies nor was it augmented by the addition of soluble CD14 or overexpression of membrane CD14. Instead, anti-TLR4 antibodies immunoprecipitated a 37-kDa protein that also bound ox-PAPC. A protein of this same size was found in aerolysin overlays used to detect GPI-anchored proteins. Therefore, these studies suggest that ox-PAPC may initially bind to a 37-kDa GPI-anchored protein, which interacts with TLR4 to induce IL-8 transcription.
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PMID:Receptors involved in the oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine-mediated synthesis of interleukin-8. A role for Toll-like receptor 4 and a glycosylphosphatidylinositol-anchored protein. 1277 73


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