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)

The addition of fMet-Leu-Phe or phorbol 12-myristate 13-acetate to human neutrophils stimulates phospholipase D activity as evidenced by the release of phosphatidic acid and the generation of diacylglycerol, and in the presence of ethanol the formation of phosphatidyl ethanol. The activation of phospholipase D by either the chemotactic factor or active phorbol ester is inhibited by the tyrosine kinase inhibitor erbstatin. The fMet-Leu-Phe-induced stimulation of this enzyme is greatly potentiated in cells which have been preincubated with low concentrations of lipopolysaccharide and serum. The presence of serum is essential for the potentiation by low concentrations of lipopolysaccharide. Moreover, the monoclonal antibody MY4(IgG2b) against CD14 inhibits the potentiation by the low concentration of lipopolysaccharide. These data suggest three important points. First, a tyrosine kinase step is necessary for the activation of phospholipase D. This suggests that the phospholipase D enzyme needs to be phosphorylated on tyrosine residues to be activated. Second, low concentrations of lipopolysaccharide, in the presence of serum, can potentiate the stimulated activity of this enzyme. Third, the priming action of the lipopolysaccharide-serum complex is mediated by CD14.
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PMID:Lipopolysaccharide in combination with serum potentiates the stimulated activity of phospholipase D in human neutrophils via CD14. 768 89

CD14, a glycosylphosphatidylinositol-anchored glycoprotein of leukocytes, binds endotoxin (lipopolysaccharide (LPS)) with high affinity. After the murine pre-B cell line 70Z/3 is transfected with DNA encoding human CD14 (hCD14), the resultant stably transfected cell line, 70Z/3-hCD14, responds to 1000-fold lower LPS concentrations than the parental CD14-negative line. We have used 70Z/3-hCD14 cells, RAW264.7 cells, and elicited murine peritoneal exudate macrophages (PEM) to study LPS-induced protein tyrosine phosphorylation. LPS induces the rapid tyrosine phosphorylation of a 38-kDa protein (p38) in 70Z/3-hCD14 cells, PEM, and RAW264.7 cells and of two isoforms of mitogen-activated protein kinases (MAPK) in only RAW264.7 cells and PEM. p38 can be distinguished from the MAPK isoforms based on differences in mobilities on SDS-polyacrylamide gel electrophoresis and the lack of reactivity of p38 with anti-MAPK antibody even after dephosphorylation with potato acid phosphatase. Synthetic lipid A induces p38 phosphorylation in 70Z/3-hCD14 cells, whereas phorbol 12-myristate 13-acetate and interferon-gamma fail to induce tyrosine phosphorylation of p38. Pretreatment of 70Z/3-hCD14 cells with anti-hCD14 monoclonal antibody or the tyrosine kinase inhibitor herbimycin A inhibits LPS-induced tyrosine phosphorylation of p38. These results suggest that increased protein tyrosine phosphorylation occurs rapidly after LPS binds to CD14 and is likely to be an important event in mediating LPS-induced cell activation.
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PMID:Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. 769 11

The product of the vav proto-oncogene, p95vav or Vav, is tyrosine phosphorylated upon stimulation of T and B cells by antigen and other receptors, and contains motifs associated with signal transduction. To determine its role in vivo, we used vav-gene-targeted embryonic stem cells and RAG-2-/- blastocyst complementation. The vav(-/-)-RAG-2-/- chimaeras displayed thymic atrophy with reduced numbers of peripheral T cells. Whereas the total number of B cells was normal, the subset of peritoneal B-1 (CD5+) cells was missing. The vav-/- T and B cells were hyporeactive when stimulated through antigen receptors, but vav-/- T cells proliferated on exposure to phorbol ester and calcium ionophore, whereas B cells responded normally to bacterial mitogen, lipopolysaccharide or the CD40 ligand. Thus, we have established here a functional role for vav in the control of T- and B-cell development and activation.
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PMID:Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. 770 Mar 59

The expression of many genes is altered upon the activation of macrophages by bacterial LPS. These genes play a crucial role in the orchestration of various responses to protect the host against infection. A novel 2.3 kilobase (kb) cDNA, designated IRG1, was obtained from a cDNA library prepared with RNA isolated from RAW 264.7 following lipopolysaccharide stimulation. Sequence analysis of the clone revealed no identity to any known genes but showed the presence of many potential phosphorylation sites suggesting that IRG1 protein product may be regulated at this level. Furthermore, IRG1 contains the motif for glycosaminoglycan attachment site, implying that IRG1 may be a proteoglycan. By interspecific back-cross analysis, Irg1 was mapped to mouse chromosome 14 linked to Tyrp2 and Rap2a. The IRG1 message appears 1.5 h following LPS exposure and its induction was not dependent on new protein synthesis. In fact, cycloheximide induced the expression of IRG1, suggesting that a protein repressor prevents the expression of IRG1 when uninduced. The role of the protein kinase A pathway in regulating the induction of IRG1 by LPS is questionable, because although forskolin inhibited its induction, neither dibutyrl-cAMP nor 8-(4-chlorophenylthio)-cAMP had much effect on its expression. In contrast, activation of protein kinase C potentiated the LPS response. Chelation of extracellular calcium inhibited IRG1 4 h after LPS induction, while increasing intracellular calcium had little effect on the levels of the IRG1 transcript. Inhibiting tyrosine phosphorylation abrogated the induction of IRG1 by LPS. Hence, the induction of IRG1 by LPS is mediated by tyrosine kinase and protein kinase C pathway.
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PMID:Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. 772 48

Although Interleukin-10 (IL-10) has been recently shown to modulate lipopolysaccharide (LPS)-induced release of cytokines in human granulocytes, the intracellular signalling pathways of LPS have been only partially defined, while those of IL-10 remain unknown. The present study shows that LPS induces an increase in tyrosine phosphorylation of a discrete number of proteins, in a time- and concentration-dependent manner. In addition, IL-10 negatively influenced protein tyrosine phosphorylation in LPS-treated human polymorphonuclear leukocytes (PMN). The effect of IL-10 was evident only after 60 min LPS-stimulation and was detected by analysing either cell lysates or lysates which were previously immunoprecipitated with anti-phosphotyrosine antibodies. Amongst the tyrosine phosphoproteins mostly affected by IL-10 in LPS-stimulated cells were the species with molecular weights ranging from 46 to 49 kDa. The identity and possible function of these proteins remain unknown. Taken together, our results suggest that tyrosine phosphorylation may constitute one of the intracellular events that mediate LPS and IL-10 responses in granulocytes.
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PMID:Interleukin-10 decreases tyrosine phosphorylation of discrete lipopolysaccharide-induced phosphoproteins in human granulocytes. 772 68

A common basis to genetic regulation of leishmanial and mycobacterial infections is provided by the action of the murine Lsh/Ity/Bcg gene in controlling the priming/activation of macrophages for antimicrobial activity. This relies on the TNF-alpha-dependent sustained expression of the inducible nitric oxide synthase (iNOS) gene responsible for the generation of large amounts of toxic nitric oxide (NO). The Lsh/Ity/Bcg gene has many pleiotropic effects, including differential expression of the early response gene KC following stimulation of macrophages with bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM). The major signal transduction pathway involved in KC induction requires the generation of low levels of NO via constitutive nitric oxide synthase (cNOS) activity, leading to activation of guanylate cyclase and the cGMP-dependent kinase pathway. NO therefore appears to provide a common link between the early influence of Lsh in regulating the expression of genes which mediate many pleiotropic effects, and the later production of NO as the final effector mechanism for kill. The recently cloned candidate for Lsh/Ity/Bcg, designated Nramp for Natural resistance associated macrophage protein, encodes a polytopic integral membrane protein that has structural features common to prokaryotic and eukaryotic transporters and includes a conserved binding-protein-dependent transport motif which may be involved in interaction with peripheral ATP-binding subunits. The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues. 773 96

Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX-2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti-inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX-2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)-stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56lyn, a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by radicicol in macrophages. Radiciciol also suppressed the COX-2 expression induced by IL-1 beta in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for radicicol. Radicicol did not inhibit the COX-2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that radicicol inhibits COX-2 expression mainly at post-transcriptional steps.
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PMID:Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis. 789 Jun 56

Mammalian cells respond to endotoxic lipopolysaccharide (LPS) by activation of protein kinase cascades that lead to new gene expression. A protein kinase, p38, that was tyrosine phosphorylated in response to LPS, was cloned. The p38 enzyme and the product of the Saccharomyces cerevisiae HOG1 gene, which are both members of the mitogen-activated protein (MAP) kinase family, have sequences at and adjacent to critical phosphorylation sites that distinguish these proteins from most other MAP kinase family members. Both HOG1 and p38 are tyrosine phosphorylated after extracellular changes in osmolarity. These findings link a signaling pathway in mammalian cells with a pathway in yeast that is responsive to physiological stress.
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PMID:A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. 791 33

Development of a congenic BALB/c mouse strain that contains a segment of chromosome 4 including the Lpsd allele of the lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ strain is presented. On the basis of LPS-induced spleen cell mitogenesis, macrophage tumor necrosis factor secretion, and tyrosine phosphorylation in vitro and lethality in galactosamine-sensitized mice in vivo, the C.C3H-Lpsd strain provides a model of LPS hyporesponsiveness that is comparable to that of the parental C3H/HeJ strain. Analysis of markers in this region indicates that length of the donor fragment is approximately 5.5 centimorgans. Thus, the C.C3H-Lpsd strain provides an important genetic tool for analysis of markers in this region and for examining functional effects of Lpsd expression on the BALB/c background.
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PMID:Construction of a BALB/c congenic mouse, C.C3H-Lpsd, that expresses the Lpsd allele: analysis of chromosome 4 markers surrounding the Lps gene. 792 9

The plasminogen activator inhibitor PAI-1 is markedly elevated in vivo and in vitro upon exposure to the inflammatory mediators tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and bacterial lipopolysaccharide. Here we report that the isoflavone compound genistein prevents the increase in synthesis of PAI-1 induced by these inflammatory mediators in human endothelial cells in vitro, and partially reduces the basal PAI-1 production by these cells. These effects of genistein were accompanied by a decrease in PAI-1 mRNA and in a suppression of the PAI-1 transcription rate as shown by run-on assay. A specific action of genistein, probably by inhibiting a tyrosine protein kinase, is likely, because the structural genistein analogue daidzein, which has a low tyrosine protein kinase inhibitor activity, did not inhibit PAI-1 synthesis. Vanadate, a tyrosine protein phosphatase inhibitor, increased PAI-1 production. The effect of genistein on PAI-1 synthesis was rather selective. Herbimycin A also reduced PAI-1 synthesis, but several other tyrosine protein kinase inhibitors, namely tyrphostin A47, methyl-2,5-dihydroxy-cinnamate, and compound 5, were unable to do so. All these tyrosine protein kinase inhibitors reduced basic fibroblast growth factor (b-FGF)-induced [3H]thymidine incorporation in endothelial cells. This indicates that the effect of genistein on PAI-1 transcription proceeds independently of its effect on mitogenesis. In contrast to TNF-alpha-induced PAI-1 production, the transcription and synthesis of urokinase-type plasminogen activator (u-PA) was not inhibited by genistein. A TNF-alpha-mutant (Trp32Thr86TNF alpha) that specifically recognizes the 55-kD TNF-receptor, mimicked the effects of TNF alpha on both PAI-1 and u-PA. Because genistein affected PAI-1, but not u-PA induced by this mutant, involvement of different TNF-receptors cannot underlie the difference in the effects of genistein on PAI-1 and u-PA synthesis. Because genistein also inhibited PAI-1 induction by thrombin and IL-4, it is likely that genistein does not act on a TNF alpha-receptor-coupled protein kinase but on the signal transduction pathway enhancing PAI-1 transcription. Our results suggest that the TNF alpha-induced signal transduction pathway of PAI-1 transcription involves a genistein-sensitive step that is not involved in the induction of u-PA by TNF alpha. Given the limited sensitivity to several other tyrosine protein kinase inhibitors, this genistein-sensitive step may be a potential target for pharmacologic intervention to reduce elevated plasma PAI-1 levels.
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PMID:Genistein reduces tumor necrosis factor alpha-induced plasminogen activator inhibitor-1 transcription but not urokinase expression in human endothelial cells. 794 70


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