Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously cloned the murine homolog of cDNA for the human myelomonocytic differentiation antigen, CD14. We synthesized three hydrophilic peptides derived from the predicted amino acid sequence of murine CD14 (mCD14), designated MS7.1, MS7.2, and MS7.3, respectively, and raised antisera against them. Each antiserum showed specific reactivity to the same peptide used for immunization. One of the anti-mCD14 antisera directed against MS7.3 peptide (AMS7.3) demonstrated the highest titer and definitively reacted with monocytic cell lines, inflammatory polymorphonuclear cells, and macrophages. Significant cross-reactivity of AMS7.3 was observed in the human monocytic cell line, THP-1. COS-1 cells transfected with MS7 cDNA expressed an antigen recognized by AMS7.3. Resident peritoneal and alveolar macrophages both expressed mCD14. mCD14 expression in peritoneal but not alveolar macrophages increased after treatment with lipopolysaccharide. Expression of mCD14 varied among monocytic cell lines and roughly paralleled the mRNA levels except in MI cells. SDS-PAGE and isoelectric focusing analysis of immunoprecipitated mCD14 showed that mCD14 was a 53 kd disulfide-linked protein with a pI of 4.5-5.1. Reduction of molecular weight by endo F treatment demonstrated that mCD14 was an N-linked glycoprotein. Since mCD14 is shed from the cell surface membrane by phosphatidylinositol-specific phospholipase C treatment, the indication is that mCD14 is a phosphatidylinositol-linked protein. The soluble form of mCD14 was detectable. Treatment with anti-mCD14 before interferon gamma (IFN gamma) stimulation significantly enhanced IFN gamma-induced H-2 antigen expression in the macrophage cell line.
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PMID:Molecular and physiological properties of murine CD14. 170 50

The macrophage scavenger receptor, a 220-kDa trimeric membrane glycoprotein, mediates the internalization of modified forms of low density lipoprotein (LDL) such as acetyl-LDL and oxidized-LDL and thus is likely to play a key role in atheroma macrophage foam cell formation. In addition, recent evidence suggests that the scavenger receptor may be an important macrophage binding site for lipopolysaccharide involved in lipopolysaccharide scavenging by macrophages. However, little is known about the regulation of this important receptor. We now report that the induction of scavenger receptor activity (as measured by acetyl-LDL stimulation of intracellular cholesterol esterification) seen in phorbol ester-differentiated THP-1 human macrophages was completely suppressed to the level seen in undifferentiated THP-1 monocytes by picomolar concentrations of transforming growth factor-beta 1 (TGF-beta 1). 125I-Acetyl-LDL degradation was inhibited in a dose-dependent manner by TGF-beta 1, with maximal inhibition (approximately 70%) occurring at 24 pM TGF-beta 1. Scatchard analysis revealed that TGF-beta 1 treatment resulted in a approximately 2-fold decrease in receptor number, and Northern blot analysis of RNA isolated from differentiated THP-1 macrophages demonstrated approximately 2-fold less scavenger receptor mRNA in TGF-beta 1-treated cells compared with that in macrophages not treated with TGF-beta 1. Since TGF-beta 1 is thought to be present in both atherosclerotic and inflammatory lesions, the above findings may have physiological relevance regarding the regulation of atheroma foam cell formation and/or the regulation of lipopolysaccharide clearance by macrophages.
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PMID:Transforming growth factor-beta 1 inhibits scavenger receptor activity in THP-1 human macrophages. 174 79

Recent studies have demonstrated the expression of messenger RNA (mRNA) for several cytokines within atherosclerotic arteries. Since cytokines have been shown to modulate functions of cultured arterial wall cells in a manner that could influence atherogenesis, this suggests that factors that modulate cytokine production would influence the atherosclerotic process. To examine whether lipoproteins can modulate cytokine production, the effect of lipoproteins on mouse macrophage interleukin-1 beta (IL-1 beta) mRNA expression was examined by dot blot and Northern blot analyses. Low density lipoprotein (LDL), acetylated-LDL, or malondialdehyde-LDL did not induce IL-1 beta mRNA expression or affect the expression in response to lipopolysaccharide (LPS). Similarly, copper ion-oxidized LDL did not stimulate the production of IL-1 beta mRNA. However, oxidized LDL inhibited the LPS-induced expression in a concentration- and time-dependent manner with a maximum inhibition (greater than 90%) observed after a 2.5 h preincubation with 25 micrograms protein/ml. These conditions did not affect protein synthesis or phagocytosis and the inhibition was partially reversible after 24 h, which together suggest that the inhibition was not due to cell death. An inhibition of IL-1 alpha and IL-6 mRNA expression was also observed while there was no change in gamma-actin mRNA levels. The level of inhibition of IL-1 beta mRNA was dependent upon the extent of LDL oxidation, but did not correlate with recognition by the scavenger receptor. A non-receptor pathway was supported by two lines of evidence: 1) the inhibition could be reproduced with a lipid extract, and 2) oxidized LDL also inhibited scavenger receptor negative THP-1 cell IL-1 beta mRNA expression. Finally, oxidized LDL had no effect on the turnover of IL-1 beta mRNA, suggesting that the decreased accumulation of IL-1 beta mRNA is due to a decrease in gene transcription. Together these studies suggest that as macrophages become foam cells their immune responsiveness is attenuated.
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PMID:Inhibition of lipopolysaccharide-induced interleukin-1 beta mRNA expression in mouse macrophages by oxidized low density lipoprotein. 181 21

Tissue factor (TF) is transiently expressed in human monocytes exposed to the inflammatory agonist bacterial lipopolysaccharide (LPS). Since TF is the major cellular initiator of the coagulation protease cascades, it is inferred that its expression within the vasculature is strictly regulated. In this study, we investigated mechanisms which control TF mRNA expression in the human monocytic cell line THP-1. LPS induced a rapid and transient accumulation of the mature 2.2-kb TF mRNA, which was maximal at 2 h. After stimulation, the rate of transcription of the TF gene was increased (3.3 +/- 1.3)fold. In addition, we observed a significant change in TF mRNA stability: at 1 h after LPS stimulation, TF mRNA was stable during a 60-min period and had a half-life of greater than 120 min, whereas at 2 h, the half-life had declined to 25 +/- 5 min. Furthermore, a larger (3.4-kb) TF RNA species was induced in these cells; the size of this species and data from selective hybridizations with intron-specific probes are consistent with the presence of an unspliced copy of intron 1. These results demonstrate that the LPS-induced accumulation of TF mRNA levels in these monocytic cells is accomplished by both transcriptional and posttranscriptional control mechanisms.
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PMID:Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. 187 49

Unlike agonists such as cytokines or hormones, the biological activity of bacterial lipopolysaccharide (LPS) is substantially modified by serum proteins. One such interaction in serum is with high-density lipoprotein (HDL) forming LPS-HDL complexes. LPS-HDL complexes have been previously shown to have reduced endotoxic activity, for example pyrogenicity, when compared to other forms of LPS in animal models. In this study, we report results of studies comparing the potency of LPS-HDL complexes with uncomplexed LPS as agonists for interleukin-1 (IL-1) production by two different sources of monocytes. LPS-HDL complexes were purified by ultracentrifugation in sodium bromide gradients. The human monocytic cell line THP-1 and the freshly isolated human monocytes, purified by adherence or elutriation from venous blood from healthy donors, were exposed to medium alone containing 1 mg/ml bovine serum albumin, HDL, LPS (parent LPS) and LPS-HDL complexes. mRNA level was analyzed on Northern blot, and cell-associated protein and supernatants were tested for IL-1 production using immunologic and biologic assays. LPS stimulates substantially more IL-1 mRNA and cell-associated IL-1 protein when the monocytes are stimulated with LPS alone versus LPS-HDL. These data suggest that LPS-HDL complexation may contribute to a reduction in endotoxic activities in vivo by preventing LPS (lipid A) from generating important transmembrane signals after binding to cells.
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PMID:Modulation of endotoxic activity of lipopolysaccharide by high-density lipoprotein. 193 Jun 90

Although monocytic cells can provide a reservoir for viral production in vivo, their regulation of human immunodeficiency virus type 1 (HIV-1) transcription can be either latent, restricted, or productive. These differences in gene expression have not been molecularly defined. In THP-1 cells with restricted HIV expression, there is an absence of DNA-protein binding complex formation with the HIV-1 promoter-enhancer associated with markedly less viral RNA production. This absence of binding was localized to the NF-kappa B region of the HIV-1 enhancer; the 65-kDa plus 50-kDa NF-kappa B heterodimer was preferentially lost. Adding purified NF-kappa B protein to nuclear extracts from cells with restricted expression overcomes this lack of binding. In addition, treatment of these nuclear extracts with sodium deoxycholate restored their ability to form the heterodimer, suggesting the presence of an inhibitor of NF-kappa B activity. Furthermore, treatment of nuclear extracts from these cells that had restricted expression with lipopolysaccharide increased viral production and NF-kappa B activity. Antiserum specific for NF-kappa B binding proteins, but not c-rel-specific antiserum, disrupted heterodimer complex formation. Thus, both NF-kappa B-binding complexes are needed for optimal viral transcription. Binding of the 65-kDa plus 50-kDa heterodimer to the HIV-1 enhancer can be negatively regulated in monocytes, providing one mechanism restricting HIV-1 gene expression.
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PMID:Negative regulation of human immunodeficiency virus type 1 expression in monocytes: role of the 65-kDa plus 50-kDa NF-kappa B dimer. 194 56

Neutrophil enzymes have been implicated as a source of lung injury in patients with the adult respiratory distress syndrome (ARDS) and with emphysema. We studied a human alveolar macrophage-derived peptide messenger, the enzyme-releasing peptide (ERP), which causes neutrophils to secrete their enzymes. The secretion and synthesis of ERP was studied in human alveolar macrophages and in the macrophage-like cell lines THP-1, HL-60, and U937. All four cell types secrete an ERP-like peptide. THP-1 cells secrete a higher concentration of the peptide than do macrophages. The secretion of ERP by THP-1 is suppressed by the protein synthesis inhibitors actinomycin D and cycloheximide. While the macrophages secrete ERP, they do not synthesize it. These studies suggest that ERP is synthesized by an alveolar macrophage precursor and stored in the mature macrophage for later release. 12-O-tetradecanoylphorbol-13-acetate (TPA) suppresses ERP secretion by THP-1 cells, but it does not modify secretion in macrophages. Escherichia coli-derived lipopolysaccharide and dimethyl sulfoxide do not modify secretion in either cell type. The THP-1 cells secrete a high- and low-mass-ratio (Mr) form of ERP-like proteins. The low Mr but not the high Mr form stimulates neutrophils to secrete their granule enzymes. We conclude that human alveolar macrophages secrete ERP but do not synthesize it. It is likely that ERP is made by an alveolar macrophage precursor in a high Mr form that is cleaved prior to secretion by the macrophages.
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PMID:Synthesis and secretion of high- and low-molecular-weight forms of the enzyme-releasing peptide (ERP) from the macrophage-like cell line THP-1. 198 75

An investigation was undertaken to determine whether a recombinant gp160 envelope protein, which is currently being evaluated as a vaccine for AIDS, induces or modulates the production of tumour necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). Incubation of monocytes from healthy, HIV-seronegative persons with 0.0001-1.0 micrograms of the recombinant vaccine did not result in the secretion of TNF-alpha or IL-1 beta, nor did the recombinant product augment or suppress monokine production by lipopolysaccharide (LPS) stimulated monocytes. The vaccine was also without a stimulatory or modulatory effect upon TNF-alpha or IL-1 beta secretion by monocytes from a patient with the AIDS-related complex (ARC) and from the monocytic THP-1 cell line. The lack of effect of gp160 on monokine production has important implications for its efficacy as a vaccine for AIDS.
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PMID:Effect of a recombinant HIV gp160 vaccine on monokine production. 199 54

Determination of neopterin [D-erythro-6-(1',2',3'-trihydroxypropyl)pterin] in body fluids is a powerful diagnostic tool in a variety of diseases in which activation of cellular immune mechanisms is involved, such as certain malignancies, allograft rejection, and autoimmune and infectious diseases. In vitro, neopterin is released into the supernatant by peripheral blood-derived monocytes/macrophages upon stimulation with gamma-interferon. In parallel, cleavage of tryptophan by indoleamine 2,3-dioxygenase is induced. We report here that the human myelomonocytic cell line THP-1 forms neopterin and degrades tryptophan upon treatment with gamma-interferon. Like in macrophages alpha-interferon and beta-interferon induce these pathways only to a much smaller degree. The action of interferons is enhanced by cotreatment with tumor necrosis factor alpha, lipopolysaccharide, or dexamethasone. gamma-Interferon-induced neopterin formation and indoleamine 2,3-dioxygenase activity are increased by raising extracellular tryptophan concentrations. The pattern of intracellularly formed pteridines upon stimulation with gamma-interferon shows the unique characteristics of human monocytes/macrophages. Neopterin, monapterin, and biopterin are produced in a 50:2:1 ratio. Thus, the THP-1 cell line provides a permanent, easily accessible in vitro system for studying the induction and mechanism of neopterin formation.
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PMID:Neopterin formation and tryptophan degradation by a human myelomonocytic cell line (THP-1) upon cytokine treatment. 211 May

The acute monocytic leukemia cell line, THP-1, is frequently used as a model to study the mechanism of cell-mediated immune response. The model is justified, in part, because THP-1 cells can be induced to express features of activated peripheral blood monocytes or tissue macrophages. The current investigation, however, demonstrates that THP-1 cells differ from normal monocytes in their secretion of interleukin-1 beta (IL-1 beta) following exposure to reagents that induce synthesis. For example, LPS treatment alone did not result in IL-1 beta secretion and very low concentrations were observed when lipopolysaccharide (LPS)-treated cells were simultaneously incubated with silica or silica in combination with hydroxyurea. Silica-enhanced release of IL-1 was related to changes in cell membrane permeability. Recombinant interferon-gamma (rIFN gamma) alone did not induce IL-1 beta secretion and did not significantly increase secretion by LPS- and silica-stimulated cells. In contrast, mezerein stimulation led to higher extracellular concentrations of IL-1 beta and rIFN gamma augmented secretion by mezerein-treated cells. Isoelectrofocusing of conditioned medium and titration of pooled fractions showed a direct correlation between extracellular levels of biologically active and immunoreactive IL-1. The role of IFN gamma in stimulating IL-1 beta secretion was not related to an enhancement of viability or an increase in the proportion of mezerein-treated cells synthesizing DNA. It was concluded that mezerein's regulation of secretion by THP-1 cells depended on the expression of monocyte features, including cell adherence and responsiveness to IFN gamma.
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PMID:Secretion of interleukin-1 beta by a leukemia cell line in response to lipopolysaccharide and mezerein. 211 75


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