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)

Like other tetraacyl partial structures of lipopolysaccharide (LPS) and lipid A, LPS that has been partially deacylated by acyloxyacyl hydrolase can inhibit LPS-induced responses in human cells. To identify the site(s) of inhibition in the LPS recognition pathway, we analyzed the apparent binding affinities and interactions of 3H-labeled enzymatically deacylated LPS (dLPS) and [3H]LPS with CD14, the LPS receptor, on THP-1 cells. Using (i) incubation conditions that prevented ligand internalization and (ii) defined concentrations of LPS binding protein (LBP), which facilitates LPS and dLPS binding to CD14, we found that dLPS can antagonize LPS in at least three ways. 1) When the concentration of LBP in the medium was suboptimal for promoting LPS-CD14 binding, low concentrations of dLPS were able to compete with LPS for binding CD14, suggesting competition between LPS and dLPS for engaging LBP. 2) When LBP was present in excess, dLPS could compete with LPS for binding CD14, but only at dLPS concentrations that were at or above its KD for binding CD14 (100 ng/ml). 3) In contrast, substoichiometric concentrations of dLPS (1 ng/ml) inhibited LPS-induced (3 ng/ml) interleukin-8 release without blocking LPS binding to CD14. Functional antagonism was possible without competition for cell-surface binding because both LPS-induced interleukin-8 release and dLPS inhibition occurred at concentrations that were far below their respective CD14 binding KD values. In addition to its expected ability to compete with LPS for binding LBP and CD14, dLPS thus potently antagonizes LPS at an undiscovered site that is distal to LPS-CD14 binding in the LPS recognition pathway.
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PMID:Enzymatically deacylated lipopolysaccharide (LPS) can antagonize LPS at multiple sites in the LPS recognition pathway. 753 70

This study evaluates the ability of the immunosuppressive drugs dexamethasone, cyclosporine, FK506 and rapamycin, alone and in combination to suppress interleukin-1 beta (IL-1 beta) secretion in vitro by THP-1 cells when stimulated by lipopolysaccharide. All four drugs, when added to cell culture medium at therapeutic concentrations, significantly decrease secretion of the monokine to well below control levels. However, only dexamethasone completely suppresses IL-1 beta secretion in a dose-dependent fashion. Cyclosporine, FK506 and rapamycin only partially suppress secretion of IL-1 beta at concentrations within their therapeutic ranges and increasing concentrations of the drugs do not result in further suppression of secretion. Likewise, the combination of any two of these three drugs does not provide any additional suppressive effect. Dexamethasone, however, when added in increasing concentrations in combination with any of the other drugs, results in further suppression of IL-1 secretion in a dose-dependent fashion. These data suggest that cyclosporine, FK506 and rapamycin all share a common effect on the production of IL-1 beta, different from that of dexamethasone.
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PMID:Modulation of interleukin-1 secretion by immunosuppressive drugs, alone and in combination. 755 78

We studied tissue transglutaminase (TGase) expression in human myelomonocytic leukemia cells treated by combinations of all-trans retinoic acid (RA) and 1,25 dihydroxyvitamin D3 (VD). We found that in U937 cells, as in HL-60 and THP-1 cells, RA alone caused an early induction of enzyme activity, correlated with increased mRNA expression. VD alone also induced rapid TGase mRNA expression but in this case TGase enzymatic activity was not measurable until 96 h following onset of treatment. Combinations of both agents had no additional effects over those of RA alone on HL-60 cells, THP-1, and U937 cells during the first 48 h. However, following further incubation, U937 cells expressed increased levels of TGase when treated by both agents. By many criteria, including their sensitivity to various inducers of oxidative burst, lipopolysaccharide-induced production of monokines and in the present work, lysozyme secretion and TGase expression, U937 cells exposed to combinations of RA and VD exhibit a behavior different from those of HL-60 and THP-1 cells. They represent a type of leukemia cell amenable by this treatment to a stage close to that of a terminally differentiated macrophage.
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PMID:Differentiation of U937 myelomonocytic cell line by all-trans retinoic acid and 1,25-dihydroxyvitamin D3: synergistic effects on tissue transglutaminase. 756 22

Expression of tumor necrosis factor alpha (TNF) by lipopolysaccharide-treated human monocytic cells is inhibited by bicyclic imidazoles. We studied the mechanism of action of a representative inhibitor, SK&F 86002, on synthesis of TNF by THP-1 cells. Levels of TNF protein were lowered by SK&F 86002 under conditions where TNF mRNA accumulation was unaffected, suggesting a post-transcriptional action. No effect of SK&F 86002 was detected on the rate of induction of TNF mRNA or steady state levels over a 5 hr period. The kinetics of SK&F 86002 inhibition of TNF protein synthesis coincided with those of anisomycin, not with actinomycin, suggesting an effect of SK&F 86002 on TNF mRNA translation. By using sucrose gradient sedimentation, we showed that quiescent THP-1 cells contained a substantial amount of TNF mRNA which was primarily associated with 43S pre-ribosomal complexes. Activation of the cells with lipopolysaccharide caused an elevation of the TNF mRNA level and increased the proportion associated with polyribosomes. Treatment with lipopolysaccharide plus SK&F 86002 led to a marked accumulation of TNF mRNA in the 43S complex-containing fractions and a concomitant reduction of polysome-associated TNF message. Neither lipopolysaccharide nor SK&F 86002 affected the amount or distribution of cyclophilin mRNA in the same fractions. The results suggest that lipopolysaccharide activates TNF translation at the initiation step and that SK&F 86002 inhibits this activation.
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PMID:Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor alpha. 758 62

We investigated the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of scavenger receptors in human monocytic cell line (THP-1 cells) treated for 24 h with 12-O-tetradecanoylphorbol-13-acetate (TPA) which induces their differentiation into macrophages. The capacity to degrade 125I-labeled acetyl low density lipoprotein (LDL) was developed in accordance with macrophage differentiation. The treatment with 10 nM 1,25(OH)2D3 for 72 h inhibited the degradation of acetyl LDL by THP-1 macrophages in a dose-dependent manner, suggesting that 1,25(OH)2D3 inhibits scavenging function in macrophages. In order to clarify the mechanism of its inhibitory effect on degradation of acetyl LDL, we performed the ligand binding assay using 125I-labeled acetyl LDL. Scatchard analysis revealed that 1,25(OH)2D3 decreased the number of scavenger receptors without changing the affinity for acetyl LDL. We next examined the effect of 1,25(OH)2D3 on the expression of scavenger receptor mRNA. The mRNA of type I scavenger receptor was first detected in THP-1 cells 4 days after the treatment with TPA, the mRNA level increased up to 6 days, and then decreased. The treatment with 1,25(OH)2D3 for 72 h dramatically decreased the mRNA levels after the acquisition of macrophage phenotypes as evidenced by nonspecific esterase staining. However, 1,25(OH)2D3 did not affect the activity of nonspecific esterase nor the induction of interleukin-1 beta mRNA by lipopolysaccharide in THP-1 macrophages. These findings suggest that 1,25(OH)2D3 exclusively decreases the expression of scavenger receptors in TPA-induced THP-1 macrophages without affecting the basic cellular functions as macrophages.
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PMID:Effect of 1,25-dihydroxyvitamin D3 on induction of scavenger receptor and differentiation of 12-O-tetradecanoylphorbol-13-acetate-treated THP-1 human monocyte like cells. 759 34

Airway inflammation is an important aspect of asthma. Recent studies of airway inflammation in asthma have focused attention on cytokines released by T helper lymphocyte type 1 (Th1)- and Th2-like T cells. Interleukin (IL)-1 is also increased in the airways of asthmatics, and it is most likely derived from airway and alveolar macrophages. The effects of Th1 or Th2 cytokines on the release of IL-1 or its specific antagonist, IL-1ra, have not been well studied. We examined the response of THP-1 cells, a myelomonocytic cell line, to stimulation with various Th1 and Th2 cytokines and found that IL-4, IL-10, and IFN-gamma increased IL-1ra mRNA and protein release. The increase in mRNA was not due to an increase in IL-1ra mRNA stability. IL-4 (10 ng/ml) increased IL-1ra release from 9,641 +/- 322 [from cells stimulated with lipopolysaccharide (LPS) alone] to 50,796 +/- 1,917 pg/ml (from cells stimulated with LPS and IL-4). IL-10 (10 ng/ml) caused a similar upregulation of IL-1ra from LPS-stimulated cells: 87,478 +/- 7,808 compared with 8,004 +/- 1,166 pg/ml released from the cells stimulated with LPS alone. Cells stimulated with IFN-gamma (100 U/ml) and LPS released 27,854 +/- 3,626 pg/ml of IL-1ra, compared with 9,069 +/- 236 pg/ml in the presence of LPS alone. In addition, the Th1 cytokine, IFN-gamma, but not the Th2 cytokines, IL-4 and IL-10, upregulated IL-1 beta mRNA and increased the release of IL-1 beta protein. Similar studies were performed using freshly isolated monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of interleukin-1 receptor antagonist by Th1 and Th2 cytokines. 763 20

In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We assessed the possibility of using such metabolic alterations for the in vitro detection of pyrogens. Products from gram-negative and gram-positive bacteria and related synthetic compounds were tested for their potential to induce either of these pathways. Stimulation of pteridine biosynthesis was monitored as the formation of neopterin in the human myelomonocytic cell line THP-1. The formation of nitric oxide was determined as nitrite in murine J774A.1 macrophage cultures. The substances tested included toxic and detoxified parts of LPS and lipid A from Escherichia coli, Salmonella typhimurium, Salmonella minnesota, and Klebsiella pneumoniae as well as lipoteichoic acid and toxic shock syndrome toxin 1 from Staphylococcus aureus. Furthermore, two cell wall compounds from Mycobacterium tuberculosis, trehalose 6,6'-dimycolate and N-acetylmuramyl-L-alanyl-D-isoglutamine, which are active components of Freund's adjuvant, were used. When applied as a single stimulus, only the whole LPS molecule potently stimulated neopterin or nitrite formation. Lipid A and products from gram-positive bacteria were weakly active. For neopterin formation, lipid A required the presence of fetal calf serum. Besides detoxified LPS and independently from the presence of serum, all bacterial compounds tested strongly increased the effects mediated by IFN-gamma. Our results show that bacterial pyrogens can be detected by monitoring the formation of neopterin or nitrite. This may provide a basis for the development of an in vitro assay for the detection of pyrogenic contamination with the aim of replacing the currently used animal test.
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PMID:Detection of bacterial pyrogens on the basis of their effects on gamma interferon-mediated formation of neopterin or nitrite in cultured monocyte cell lines. 766 77

Macrophage adherence, an important regulatory signal, has the potential to affect human immunodeficiency virus (HIV) production either directly or by priming monocytes to respond to other activating signals. We have investigated the role of adherence as an activator of HIV-1 transcription and release. The effects of adherence on HIV-1 transcription were examined by using THP-1 cells, a human monocytic cell line, transfected with HIV long terminal repeat (LTR)-chloramphenicol acetyltransferase (CAT) constructs. The effects of adherence on release of HIV-1 were investigated in both HIV-1-infected THP-1 cells and human peripheral blood monocyte-derived macrophages (MDM). Adherence of lipopolysaccharide (LPS)-stimulated THP-1 cells to either tissue culture plastic or endothelial cells was crucial for enhanced HIV-1 transcription as measured by LTR-CAT expression. Such increased LTR-CAT expression did not occur with an HIV LTR construct containing mutated NF-kappa B binding sites. In contrast, release of whole HIV, measured by reverse transcriptase (RT) activity in tissue culture medium, was reduced upon adherence of stimulated HIV-1-infected THP-1 cells without suppression of HIV LTR-CAT transcription or p24 release. This finding suggested that activation of adherent monocytic cells interfered with HIV assembly and release. Although the reduction of RT activity following activation of HIV-1-infected MDM was independent of adhesion, adherence alone of nonstimulated HIV-infected MDM to endothelial cells was sufficient to induce a reduction in RT release. This study demonstrates that LPS stimulation of monocytic cells enhances HIV LTR transcription under adherent conditions. In contrast, activation of adherent monocytic cells infected with HIV reduced viral release.
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PMID:Release of human immunodeficiency virus by THP-1 cells and human macrophages is regulated by cellular adherence and activation. 768 70

The cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) are released by mononuclear phagocytes in vitro after stimulation with mycobacteria and are considered to mediate pathophysiologic events, including granuloma formation and systemic symptoms. We demonstrated that the Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM) is a very potent inducer of IL-1 beta gene expression in human monocytes and investigated the mechanism of this effect. We localized the LAM-, lipopolysaccharide (LPS)-, and TNF-alpha-inducible promoter activity to a -131/+15 (positions -131 to +15) DNA fragment of the IL-1 beta gene by deletion analysis and chloramphenicol acetyltransferase assay. Within this DNA fragment, there were two novel 9-bp motifs (-90/-82 and -40/-32) with high homology to the nuclear factor-IL6 (NF-IL6) binding site. Site-directed mutagenesis demonstrated that the two NF-IL-6 motifs could be independently activated by LAM, LPS, or TNF-alpha and that they acted in an orientation-independent manner. DNA mobility shift assay revealed specific binding of nuclear protein(s) from LAM-, LPS-, or TNF-alpha-stimulated THP-1 cells to the NF-IL6 motifs. We conclude that the two NF-IL6 sites mediate induction of IL-1 beta in response to the stimuli LAM, LPS, and TNF-alpha.
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PMID:Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. 768 3

Prostacyclin analogues have been reported to inhibit the expression of tissue factor procoagulant activity in human monocytes, primarily by elevating intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP). The present studies have investigated whether prostacyclins can also inhibit tissue factor expression in endothelial cells. Iloprost, carbacyclin, and ciprostene had no effect on human umbilical vein endothelial tissue factor activity induced by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 beta (IL-1 beta). Iloprost failed to elevate intracellular levels of cAMP, even when combined with a phosphodiesterase inhibitor. In contrast, forskolin increased endothelial cAMP and inhibited tissue factor expression. Conditioned medium from LPS-challenged monocytic THP-1 cells, which contained both TNF-alpha and IL-1 beta, induced endothelial cell procoagulant activity to levels 20-fold higher than those achieved in response to LPS alone. Iloprost abolished LPS-induced TNF-alpha secretion by THP-1 cells and inhibited IL-1 beta secretion by 45%. In keeping with this, iloprost reduced levels of TNF-alpha and IL-1 beta mRNA in LPS-challenged cells. Treatment of THP-1 cells with iloprost strongly inhibited the ability of conditioned medium to induce endothelial tissue factor expression, an effect that was mimicked by treating the medium with blocking antibodies to the cytokines. We conclude that although prostacyclin analogues do not directly suppress endothelial tissue factor expression due to their failure to elevate cAMP, they may do so indirectly by inhibiting the amplification produced by monocyte-derived cytokines.
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PMID:Effects of prostacyclin analogues on human endothelial cell tissue factor expression. 768 94


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