UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.
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PMID:Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells. 819 1

A 2- to 3-fold increase of GTP cyclohydrolase I (E.C. 3.5.4.16), the key enzyme of tetrahydrobiopterin biosynthesis from GTP, was observed in cerebellum, remaining brain, liver, spleen, and adrenal gland of rats treated with a single dose of lipopolysaccharide (LPS). This led to increased biopterin levels in tissues but not in plasma. Parallel induction of nitric oxide (NO) synthase was indicated by a 10- to 100-fold increase of plasma nitrate levels 6 and 12 hours after injection of LPS. Furthermore, systolic blood pressure was reduced significantly by 23%. Our results demonstrate induction of tetrahydrobiopterin biosynthesis after LPS treatment in vivo.
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PMID:Induction of GTP cyclohydrolase I by bacterial lipopolysaccharide in the rat. 848 53

Interferons (IFN) and lipopolysaccharide (LPS) cause multiple changes in isoprenoid-modified proteins in murine macrophages, the most dramatic being the expression of a prenyl protein of 65 kDa. The guanylate binding proteins (GBPs) are IFN-inducible GTP-binding proteins of approximately 65 kDa that possess a CaaX motif at their C-terminus, indicating that they might be substrates for prenyltransferases. The human GBP1 protein, when expressed in transfected COS-1 cells, incorporates radioactivity from the isoprenoid precursor [3H]mevalonate. In addition, huGBPs expressed from the endogenous genes in IFN-gamma-treated human fibroblasts or monocytic cells were also found to be isoprenoid modified. IFN-gamma-induced huGBPs in HL-60 cells were not labeled by the specific C20 isoprenoid, [3H]geranylgeraniol, but did show decreased isoprenoid incorporation in cells treated with the farnesyl transferase inhibitor BZA-5B, indicating that huGBPs in HL-60 cells are probably modified by a C15 farnesyl rather than the more common C20 lipid. Differentiated HL-60 cells treated with IFN-gamma/LPS showed no change in the profile of constitutive isoprenylated proteins and the IFN-gamma/LPS-induced huGBPs remained prenylated. Despite being prenylated, huGBP1 in COS cells and endogenous huGBPs in HL-60 cells were primarily (approximately 85%) cytosolic. Human GBPs are thus among the select group of prenyl proteins whose synthesis is tightly regulated by a cytokine. HuGBP1 is an abundant protein whose prenylation may be vulnerable to farnesyl transferase inhibitors that are designed to prevent farnesylation of Ras proteins.
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PMID:Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1. 883 Aug

We investigated for the first time the effect of lipopolysaccharide and the signal transduction pathway on the biosynthesis of tetrahydrobiopterin [(6R-L-erythro-1',2'-dihydroxypropyl) -2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine], the cofactor for the enzymatic hydroxylation of the aromatic amino acids, in the murine neuroblastoma cell line N1E-115, which synthesizes tetrahydrobiopterin constitutively. Activation of N1E-115 cells with 1 microgram/ml lipopolysaccharide resulted in statistically significant increases in both intracellular tetrahydrobiopterin contents and the activity (Vmax) of GTP cyclohydrolase I, a rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis. Following simultaneous addition of the inhibitors of protein tyrosine kinases and GTP-binding proteins into serum-free culture media with lipopolysaccharide, we analyzed the transduction pathway of lipopolysaccharide signal toward the tetrahydrobiopterin biosynthetic system in N1E-115 cells. Our data indicate the following conclusions: (a) Protein tyrosine kinase systems are involved in mediating lipopoly-saccharide signal to tetrahydrobiopterin production, and (b) there may be a cross-talk between GTP-binding protein and the protein tyrosine kinase system in mediating lipopolysaccharide signal. These observations suggest that a neuronal cell such as N1E-115, which barely expresses CD14 on its cell surface, responds to lipopolysaccharide like macrophages and monocytes in the absence of soluble CD14.
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PMID:Tetrahydrobiopterin biosynthesis enhanced by lipopolysaccharide stimulation in murine neuroblastoma cell line N1E-115. 893 88

Chlamydia trachomatis is a nucleotide parasite, being entirely dependent on its host eukaryotic cell for a supply of ATP, GTP, and UTP. Chlamydiae are not, however, auxotrophic for CTP, as they are able both to transport CTP from the host and synthesize CTP de novo via a chlamydial CTP synthetase. This study addresses the developmental regulation of CTP synthetase over the course of the C. trachomatis life cycle. Given the distinct life stages of C. trachomatis, analysis of temporal changes in gene expression and regulation of protein activity is the key to unravelling the mechanism of pathogenesis of this bacterium. The results of immunodetection analysis indicate that CTP synthetase is present in C. trachomatis elementary bodies and reticulate bodies and that it is widespread in other chlamydial strains. Reverse transcriptase-polymerase chain reaction (RT-PCR) and metabolic labelling experiments show that CTP synthetase is transcribed and translated primarily during the mid- and late stages of the chlamydial growth cycle. In addition, C. trachomatis CTP synthetase was transcribed with the CTP utilizing enzyme CMP-2-keto-3-deoxy-octanoic acid synthetase (CMP-KDO synthetase) as part of a polycistronic mRNA. The co-expression of these two enzymes suggests a role for CTP synthetase in lipopolysaccharide biosynthesis, potentially channelling CTP directly to CMP-KDO synthetase. The ability of the intact operon to complement CTP synthetase and CMP-KDO deficiencies in mutant Escherichia coli strains indicates that both enzymes are efficiently translated from a single messenger RNA. Kinetic analysis revealed that the C. trachomatis CTP synthetase possessed co-operativity patterns typical of both prokaryotic and eukaryotic CTP synthetases. However, the K(m) of the enzyme for UTP was lower than that of E. coli CTP synthetase, presumably in response to the low intracellular concentration of this nucleotide in C. trachomatis.
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PMID:Chlamydia trachomatis CTP synthetase: molecular characterization and developmental regulation of expression. 895 11

To investigate the interaction between endothelin (ET) and the nitric oxide system, we examined the effects of ET-1 and ET-3 on the induction of inducible nitric oxide synthase (iNOS) and guanosine triphosphate cyclohydrolase I (GTP:CHI), the rate-limiting enzyme of de novo synthesis of the cofactor tetrahydrobiopterin (BH4), in rat mesangial cells. ET-1 inhibited the nitrite accumulation induced by a combination of interleukin-1 beta, tumor necrosis factor-alpha, and lipopolysaccharide in a concentration-dependent manner. The inhibitory effect of ET-3 was less potent than that of ET-1. A selective ETA antagonist, BQ-485, and an ETA and ETB antagonist, TAK-044, abolished the inhibitory effects of ET-1, whereas the selective ETB antagonist BQ-788 had no effect on the inhibition produced by ET-1. These observations indicate that ET-1 inhibits cytokine-stimulated nitrite accumulation through the ETA receptor. Western blot analysis showed that the suppression of nitrite accumulation was accompanied by a decrease in iNOS protein. Northern blot analysis showed that ET-1 inhibited the expression of both iNOS and GTP:CHI mRNA. In conclusion, ET-1 inhibits cytokine-stimulated nitric oxide production through the ETA receptor by suppressing the expression of iNOS and GTP:CHI mRNA in rat mesangial cells.
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PMID:Endothelin-1 inhibits induction of nitric oxide synthase and GTP cyclohydrolase I in rat mesangial cells. 895 63

In cultured granulosa cells, interleukin-1 beta (IL-1 beta) induced a time-dependent (16-72 h) and dose-related (0.3-30 ng/ml) stimulation of nitric oxide (NO) synthase (NOS) activity, as determined by the catalytic conversion of [3H]arginine to [3H]citrulline and NO2- accumulation in the culture medium. Although FSH alone failed to stimulate NOS activity, concomitant treatment with the gonadotropin (200 ng/ ml) or the cell-permeant cAMP analog (Bu)2cAMP (0.5 mM) markedly enhanced IL-1 beta-induced NO generation in cultured granulosa cells. The effect of IL-1 beta on citrulline biosynthesis and NO2- accumulation was abrogated by the NOS inhibitor NG-methyl-L-arginine or the IL-1-receptor antagonist protein. In contrast bacterial endotoxin (lipopolysaccharide), interferon-gamma, or tumor necrosis factor-alpha, which are well known inducers of inducible NOS (iNOS) in a variety of immunocompetent and nonimmunocompetent cell types, failed to increase [3H]citrulline formation or NO2- accumulation in untreated or FSH-stimulated cells. As demonstrated by reverse transcriptase-PCR analysis, IL-1 beta-stimulated NO generation was accompanied by a time-dependent increase in messenger RNA levels for iNOS and GTP-cyclohydrolase (GTPCH), the rate-limiting step for de novo tetrahydrobiopterin (BH4) biosynthesis. Treatment with FSH augmented only GTPCH messenger RNA expression, and a more than additive GTPCH signal was observed when cells were simultaneously challenged with IL-1 beta and FSH. Treatment with the GTPCH inhibitor 2,4-diamino-6-hydroxypyrimidine prevented IL-1 beta-induced NOS activity in untreated or FSH-stimulated cells, and this inhibition was completely reversed by sepiapterin, a substrate for BH4 biosynthesis, via an alternative pterin salvage pathway present in many cell types. As BH4 is an essential cofactor for NOS catalytic activity, these observations strongly suggest that FSH-induced biosynthesis of endogenous BH4 is essential for full iNOS biosynthetic capacity in IL-1 beta-stimulated granulosa cells.
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PMID:Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 beta-stimulated nitric oxide synthase activity in granulosa cells. 897

We report that gram-negative bacterial lipopolysaccharide (LPS) binds to CD14 on lipid-enriched, low-density domains of the human monocyte-macrophage (THP-1 cell) plasma membrane. After brief incubation with [3H]LPS under conditions that prevent its internalization, THP-1 cells were disrupted using a detergent-free method and plasma membrane fragments were separated on density gradients. The [3H]LPS-binding fragments had low bouyant densities and were enriched, when compared to high-density membrane fragments, in CD14 (a receptor for LPS and other microbial molecules), p53/56lyn, GTP-binding proteins, ouabain-inhibitable Na+/K+ ATPase, sphingomyelin, and GM1 ganglioside. Monoclonal anti-CD14 antibody 60bca blocked [3H]LPS binding to these membrane fragments. Immunoelectron microscopic analysis identified clusters of CD14 on both large (200-1,000 nm) and small (< or = 200 nm) low-density membrane fragments. GM1 and CD14 were usually found on the same fragments, yet their distributions on those fragments infrequently overlapped. These cells seem to lack arrays of caveolae, the ordered membrane structures that harbor glycosylphosphatidyl-anchored proteins and GM1 in many other cell types. Finding that LPS binds to CD14 predominantly in low-density plasma membrane domains suggests, however, that discrete regions of the monocyte-macrophage plasma membrane may be organized to facilitate rapid responses to, and internalization of, molecules that bind CD14.
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PMID:Bacterial lipopolysaccharide binds to CD14 in low-density domains of the monocyte-macrophage plasma membrane. 911 40

Using differential screening of cytokine-activated versus resting porcine aortic endothelial cells (PAEC), we have isolated a member of the family of Ras/GTP-binding proteins. The cDNA encodes a 34-kilodalton protein showing 97% homology to Gem, a gene recently isolated from activated T cells, likely representing its porcine homologue. The amino acid sequence differs from the Ras consensus by the absence of a C-terminal isoprenylation site and a glycine to glutamic acid substitution in the third GTP-binding domain. We report here, that pigGem mRNA is strongly inducible in PAEC upon activation by either IL-1 alpha, TNF alpha or lipopolysaccharide (LPS). Low constitutive expression is found in several organs. Epitope-tagged pigGem transfected into endothelial cells (EC) localizes to the cytoplasm and to the inner side of the plasma membrane. Structural features of Gem and its inducibility apparently restricted to T cells and endothelial cells, together with Rad, a GTPase overexpressed in skeletal muscle cells of type II diabetic individuals, define a new branch within the superfamily of GTP-binding proteins.
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PMID:Gem, a GTP-binding protein from mitogen-stimulated T cells, is induced in endothelial cells upon activation by inflammatory cytokines. 914 21

1. Nucleotide-induced currents in untreated (proliferating) and lipopolysaccharide (LPS; 100 ng ml(-1)) treated (non-proliferating) rat microglial cells were recorded by the whole-cell patch-clamp technique. Most experiments were carried out on non-proliferating microglial cells. ATP (100 nM-1 mM), ADP (10 nM-10 mM) and UTP (1 microM-100 mM), but not uridine (100 microM-10 mM) produced a slow outward current at a holding potential of 0 mV. The effect of UTP (1 mM) did not depend on the presence of extracellular Mg2+ (1 mM). The outward current response to UTP (1 mM) was similar in non-proliferating and proliferating microglia. 2. In non-proliferating microglial cells, the ATP (10 microM)-induced outward current was antagonized by suramin (300 microM) or reactive blue 2 (50 microM), whereas 8-(p-sulphophenyl)-theophylline (8-SPT; 100 microM) was inactive. By contrast, the current induced by UTP (1 mM) was increased by suramin (300 microM) and was not altered by reactive blue 2 (50 microM) or 8-SPT (100 microM). 3. The current response to UTP (1 mM) disappeared when K+ was replaced in the pipette solution by an equimolar concentration of Cs+ (150 mM). However, the effect of UTP (1 mM) did not change when most Cl- was replaced with an equimolar concentration of gluconate (145 mM). The application of 4-aminopyridine (1 mM) or Cs+ (1 mM) to the bath solution failed to alter the UTP (1 mM)-induced current. UTP (1 mM) had almost no effect in a nominally Ca2+-free bath medium, or in the presence of charybdotoxin (0.1 microM); the inclusion of U-73122 (5 microM) or heparin (5 mg ml(-1)) into the pipette solution also blocked the responses to UTP (1 mM). By contrast, the effect of ATP (10 microM) persisted under these conditions. 4. I-V relations were determined by delivering fast voltage ramps before and during the application of UTP (1 mM). In the presence of extracellular Cs+ (1 mM) and 4-aminopyridine (1 mM) the UTP-evoked current crossed the zero current level near -75 mV. Omission of Ca2+ from the Cs+ (1 mM)- and 4-aminopyridine (1 mM)-containing bath medium or replacement of K+ by Cs+ (150 mM) in the pipette solution abolished the UTP current. 5. Replacement of GTP (200 microM) by GDP-beta-S (200 microM) in the pipette solution abolished the current evoked by UTP (1 mM). 6. When the pipette solution contained Cs+ (150 mM) instead of K+ and in addition inositol 1,4,5,-trisphosphate (InsP3; 10 microM), an inward current absolutely dependent on extracellular Ca2+ was activated after the establishment of whole-cell recording conditions. This current had a typical delay, a rather slow time course and did not reverse its amplitude up to 100 mV, as measured by fast voltage ramps. 7. A rise of the internal free Ca2+ concentration from 0.01 to 0.5 microM on excised inside-out membrane patches produced single channel activity with a reversal potential of 0 mV in a symmetrical K+ solution. The reversal potential was shifted to negative values, when the extracellular K+ concentration was decreased from 144 to 32 mM. By contrast, a decrease of the extracellular Cl- concentration from 164 to 38 mM did not change the reversal potential. 8. Purine and pyrimidine nucleotides act at separate receptors in rat microglial cells. Pyrimidinoceptors activate via a G protein the enzyme phospholipase C with the subsequent release of InsP3. The depletion of the intracellular Ca2+ pool appears to initiate a capacitative entry of Ca+ from the extracellular space. This Ca2+ then activates a Ca2+-dependent K+ current.
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PMID:Coexistence of purino- and pyrimidinoceptors on activated rat microglial cells. 924 43

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