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)

Previous studies from our laboratory suggested that phorbol 12-myristate 13-acetate (TPA) stimulates prostaglandin E2 (PGE2) production by inducing de novo synthesis of prostaglandin H synthase (PHS) in a rat tracheal cell line. We report here an extension of this work to further elucidate the mechanisms by which TPA (and epidermal growth factor) stimulates PGE2 production. We used the rat tracheal cell line EGV6, which has a lower basal level of PGE2 production and responds to TPA and EGF stimulation with a much greater increase in PGE2 synthesis than the previously used cell line, Incubation of EGV6 cultures with TPA or EGF resulted in a time- and dose-dependent increase in PGE2 synthesis up to 40-fold and 6-fold, respectively. Serum also stimulated PGE2 synthesis, while bombesin, retinoic acid, and bacterial lipopolysaccharide did not. PHS protein levels in microsomal preparations from the cells were estimated by Western analysis. Antibodies raised against murine PHS-2 cross reacted with the EGV-6 PHS while several antibody preparations that react with PHS-1 from ram or mouse reacted poorly with the cellular preparation. TPA treatment increased the de novo synthesis of PHS-2 while dexamethasone treatment reduced the response to TPA. Northern blot analysis of mRNA from EGV6 cultures using a ram PHS cDNA revealed a 2.8- and a 4.5- to 4.9-kb (designated 4.9 kb) transcript. Treatment with TPA or EGF increased the expression of both transcripts and this effect was further enhanced by cyclohexamide. To further define the PHS mRNA species of EGV6 cells, two well-characterized murine PHS cDNA probes were used. The constitutive murine PHS cDNA probe hybridized only with the 2.8-kb transcript, and the inducible murine PHS cDNA hybridized only with the 4.9-kb transcript. The rates of induction as well as degradation of the 4.9-kb PHS mRNA were much more rapid than those of the 2.8-kb mRNA species. Dexamethasone partially inhibited the induction of both PHS transcripts by TPA. Southern analysis of genomic EGV6 DNA indicated the presence of two distinct PHS genes in these cells. Taken together these findings indicate that two PHS genes are expressed in rat tracheal epithelial cells. In contrast to the PHS genes expressed in murine (and chicken) fibroblasts in which only the gene coding for the larger mRNA species is transcriptionally regulated, in the rat tracheal cells both genes are positively regulated by TPA and EGF and downregulated by glucocorticoids.
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PMID:Phorbol ester and epidermal growth factor enhance the expression of two inducible prostaglandin H synthase genes in rat tracheal epithelial cells. 832 87

The mechanism by which glucocorticoids inhibit interleukin (IL)-1 and IL-6 formation in human monocytes and a promonocytic cell line activated by Escherichia coli lipopolysaccharide was analyzed. Dexamethasone (DEX) decreased levels of IL-1 alpha and IL-1 beta mRNAs in a dose-related fashion. The DEX-induced decrease in levels of IL-1 alpha and IL-1 beta mRNAs was abolished by the steroid receptor antagonist RU486. The levels of IL-1 alpha and IL-1 beta proteins within the cells and of IL-1 beta in the culture medium were decreased by DEX to comparable extents, so that DEX had no detectable effect on cytokine secretion. DEX did not influence lipopolysaccharide-induced transcription of the IL-1 beta gene in monocytes. However, DEX markedly decreased the stability of IL-1 beta mRNA, as shown both by steady state measurements and by pulse-labeling. DEX-induced instability of IL-1 beta mRNA required protein synthesis. DEX was also found to be a potent inhibitor of IL-1-induced expression of the IL-6 gene in connective tissue-type cells from the synovium of patients with rheumatoid arthritis. Inhibition of the formation of proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha, is a mechanism by which glucocorticoids exert anti-inflammatory effects. Inhibition by glucocorticoids of the expression of IL-1 alpha in antigen-presenting cells could decrease the capacity of the cells to stimulate the proliferation of T lymphocytes. This activity, as well as inhibition of the production and effects of IL-1 beta, including induced formation of IL-6 and of certain lymphokines, could explain the immunosuppressive effects of glucocorticoids.
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PMID:Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability. 842 22

Platelet-activating factor (PAF) plays an important role in a number of biological processes ranging from inflammation to reproductive biology. We have reported that the enzyme that inactivates this potent autacoid, PAF-acetylhydrolase (PAF-AH), is decreased in maternal plasma during the latter stages of pregnancy. This enzyme is associated with the plasma lipoprotein fraction and therefore its tissue origin was thought to be the liver. Prescott and colleagues (J. Biol. Chem. 265, 17381, 1990) have reported that both a rat liver cell line (HepG2 cells) and human peripheral macrophages secrete PAF-AH of the plasma type. We have shown previously that the injection of rats with dexamethasone or medroxyprogesterone causes an increase and estrogen a decrease in the plasma PAF-AH activity. To clarify the mechanism of hormonal regulation of PAF-AH production, we employed a monocyte-macrophage model system to investigate the secretion of PAF-AH during differentiation. In the present study, we have demonstrated that a myelocytic leukemic cell line (HL-60) produces and secretes PAF-AH into a defined medium when the cells are differentiated into macrophages following stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA). The medium obtained from unstimulated HL-60 cells did not contain detectable amounts of PAF-AH activity. Stimulation with TPA caused a dose- and time-dependent increase in PAF-AH activity in the media. No increase in cell number was observed in the HL-60 cells during the culture period after the cells were treated with TPA. Cell lysis was excluded by the demonstration that the TPA-induced adherent cells excluded trypan blue and did not release lactate dehydrogenase activity into the medium. The increase in PAF-AH activity was inhibited by actinomycin D and cycloheximide. Dexamethasone and medroxyprogesterone markedly increased the secretion of PAF-AH by these cells, while estrogen was without effect. Bacterial endotoxin (lipopolysaccharide, LPS) inhibited the production of PAF-AH by these cells in a dose-dependent manner. The stimulation of PAF-AH secretion during differentiation of HL-60 cells and its modulation by LPS and steroid hormones may provide a useful model system for studying PAF metabolism during the inflammatory response and pregnancy.
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PMID:Secretion of platelet-activating factor acetylhydrolase following phorbol ester-stimulated differentiation of HL-60 cells. 846 Sep 40

It has been proposed that angiotensinogen is an acute phase protein, because its plasma concentrations increase during some forms of acute inflammation. However, this is not a consistent finding. Furthermore, no specific function of circulating angiotensinogen in the inflammatory reaction is known. This may be different for extrahepatic synthesis of angiotensinogen, as the local generation of angiotensin II has been implicated in inflammation-related processes in some organs. We have therefore examined the expression of the angiotensinogen gene in liver and extrahepatic tissues under the influence of experimental inflammatory stimuli in comparison to the effects of dexamethasone. Dexamethasone (7 mg/kg intraperitoneally) induced a several-fold increase in angiotensinogen mRNA in liver, aorta, heart, adrenal, and a moderate increase in kidney, testis, and brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, whereas albumin concentrations decreased. Lipopolysaccharide (500 micrograms/kg subcutaneously) stimulated angiotensinogen mRNA in hepatic, cardiac, renal, adrenal, and testicular tissues, but not in the brain. Plasma concentrations of angiotensinogen, alpha 1-acid glycoprotein, and alpha 2-macroglobulin increased, those of albumin decreased. In turpentine-treated rats (5 ml/kg subcutaneously), angiotensinogen mRNA was reduced in liver and kidney; stimulated in adrenals, testis, and heart; and not influenced in the brain. Plasma concentrations of the acute phase proteins increased, whereas angiotensinogen and albumin decreased. It is concluded that hepatic and extrahepatic angiotensinogen gene expression seem to be regulated similarly by dexamethasone and lipopolysaccharide. The different response to turpentine may reflect differences in the pattern of cytokines induced by turpentine or be associated with additional pharmacological effects of turpentine or its metabolites.
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PMID:Tissue distribution of angiotensinogen mRNA during experimental inflammation. 849 13

One hour after lipopolysaccharide (LPS) administration (intravenous) in guinea pigs, alveolar macrophages are primed for an ex vivo increased secretion of arachidonic acid metabolites from the cyclooxygenase and the lipoxygenase pathways, with challenge by a second stimulus. At the same time, maximal levels of tumor necrosis factor-alpha (TNF-alpha) are observed in the circulation and in the bronchoalveolar lavage fluid. An extracellular form of phospholipase A2, corresponding probably to the low-molecular-mass type II enzyme, known to accumulate in inflammatory exudates, appears later in the serum of guinea pigs, to reach maximal levels 6 h after the LPS. Unlike the intracellular enzyme, extracellular phospholipase A2 is not increased by LPS in alveolar macrophages or in bronchoalveolar lavage fluids. After 24 h, at the time when neither TNF-alpha nor extracellular phospholipase A2 is present and priming of macrophages is over, maximal neutrophil infiltration is observed in the alveolar space of LPS-treated guinea pigs. Dexamethasone administered repeatedly during 3 days (subcutaneous) before the LPS challenge prevented both early events such as the macrophage priming and the TNF-alpha appearance and later events such as extracellular phospholipase A2 release and neutrophil recruitment.
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PMID:Modulation by dexamethasone of phospholipase A2 activities in endotoxemic guinea pigs. 856 72

Incubation of human A549/8 cells with human interleukin-1 beta (50 units/ml), interferon-gamma (100 units/ml), and tumor necrosis factor-alpha (10 ng/ml) (cytomix) resulted in a marked expression of the mRNA of the inducible nitric oxide synthase (NOS II). This induction was prevented by cycloheximide. Dexamethasone markedly reduced cytokine-induced NOS II mRNA concentrations; this reduction was prevented by RU 38486 (mifepristone). Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor-kappa B (NF-kappa B) activation, also significantly decreased cytomix-induced NOS II mRNA levels. When A549/8 cells were transfected with a construct containing 1570-bp 5'-flanking sequence of the murine NOS II gene cloned before a reporter gene, the murine NOS II promoter was induced up to 20-fold with cytomix but not with bacterial lipopolysaccharide. Dexamethasone as well as pyrrolidine dithiocarbamate inhibited this induction. In electrophoretic mobility shift assays, nuclear protein extracts from cytomix-induced, but not from unstimulated cells, significantly slowed the migration of an oligonucleotide containing the NF-kappa B-binding site. This band shift was markedly reduced by dexamethasone. On the other hand, cytomix-induced nuclear protein content of NF-kappa B p65 and NF-kappa B p50 was not reduced by dexamethasone (as analyzed by Western blot). Dexamethasone also did not reduce cytomix-induced expression of NF-kappa B p65 mRNA or enhance the expression of NF-kappa B inhibitor mRNA. The human and murine NOS II promoters also contain consensus sequences for activating protein-1 (AP-1) binding. However, AP-1 binding activity of nuclear extracts of A549/8 cells was not enhanced by cytomix or inhibited by dexamethasone. These data suggest that the activated glucocorticoid receptor prevents (by a protein/protein interaction) the binding of transcription factor NF-kappa B, but not AP-1, to the NOS II promoter, thereby inhibiting the induction of NOS II transcription.
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PMID:Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-kappa B. 856 1

Two carbohydrate-dependent mechanisms exist on alveolar macrophages to clear mannose-containing pathogens: receptor-mediated entry of non-opsonized microorganisms via the mannose receptor and receptor recognition of pathogens opsonized with surfactant-associated protein A (SP-A). A number of studies have demonstrated that mannose receptor expression is tightly linked to the functional state of the macrophage. In the present study, we investigated regulation of binding of SP-A to its receptor on macrophages by the same agents that regulate mannose-receptor expression. Phorbol 12-myristate 13-acetate, lipopolysaccharide (LPS), and interferon-gamma treatment of rat marrow-derived macrophages increased SP-A binding by 163, 296, and 337%, respectively, over untreated controls. Mannose-receptor activity was reduced to 75, 60, and 25% of control levels by these agents. Dexamethasone increased mannose receptor activity to 225%, while decreasing SP-A binding to 44% of controls. Addition of granulocyte macrophage-colony stimulating factor (GM-CSF) to human monocytes on day 0 dramatically increased mannose-receptor activity on day 5 over the non-serum control. SP-A binding was highest to freshly isolated monocytes and decreased to < 10% after differentiation in the presence of GM-CSF. After intraperitoneal injection of dexamethasone, rat alveolar macrophages isolated at 24 h expressed increased mannose-receptor activity and decreased SP-A binding. LPS injection resulted in increased SP-A binding and decreased mannose-receptor activity. In every instance, SP-A binding was inversely regulated with respect to mannose-receptor expression. We therefore speculate that the mannose receptor is a first-line host-defense receptor that is turned off during inflammation. SP-A in the alveolar space can then act as a lung-specific opsonin and mediate clearance of pathogens via the upregulated SP-A receptor.
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PMID:Differential regulation of the mannose and SP-A receptors on macrophages. 857 33

To examine the reported heterogeneity of endothelial cells to Shiga-like toxin 1 (Stx1), the responses of human umbilical (HUVEC) and saphenous (HSVEC) vein endothelial cells to cytokines, butyrate, and toxin were compared. Untreated HSVEC were generally more susceptible than were HUVEC to Stx1; pretreatment of either cell with lipopolysaccharide, interleukin-1 beta, or tumor necrosis factor-alpha enhanced Stx1 toxicity. Dexamethasone alone increased total globotriaosylceramide (Gb3) content and toxin binding but inhibited cytokine-enhanced cytotoxicity, whereas the differentiation agent, sodium butyrate, increased both Gb3 content and cytotoxicity responses to Stx1, most prominently in HSVEC. Stx1 toxicity directly correlated with the release of von Willebrand factor from HSVEC but not from HUVEC. Thus, HUVEC and HSVEC exhibit distinctive responses to Stx1, cytokines, and butyrate. This suggests the need for caution in extrapolating from in vitro studies utilizing one endothelial cell type to in vivo events during pathogenesis of Stx-mediated thrombotic microangiopathies.
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PMID:Comparison of the effects of Shiga-like toxin 1 on cytokine- and butyrate-treated human umbilical and saphenous vein endothelial cells. 862 68

Activation of glial cells and the consequent release of cytokines, proteins, and other intercellular signaling molecules is a well-recognized phenomenon in brain injury and neurodegenerative disease. We and others have previously described an inducible prostaglandin G/H synthase, known as PGHS-2 or cyclooxygenase-2, that is up-regulated in many cell systems by cytokines and growth factors and down-regulated by glucocorticoid hormones. In cultured mouse astrocytes we observed increased production of prostaglandin E2 (PGE2) after stimulation with either interleukin-1 beta (IL-1 beta) or the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). This increase in PGE2 content was blocked by pretreatment with dexamethasone and correlated with increases in cyclooxygenase activity measured at 4 h. Northern blots revealed concomitant increases in PGHS-2 mRNA levels that peaked at 2 h and were dependent on the dosage of IL-1 beta. Dexamethasone inhibited this induction of PGHS-2 mRNA by IL-1 beta. TPA, basic fibroblast growth factor, and the proinflammatory factors tumor necrosis factor alpha and lipopolysaccharide, but not interleukin-6, also stimulated PGHS-2 mRNA expression. Relative to IL-1 beta, the greater increases in PGE2 production and cyclooxygenase activity caused by TPA correlated with a greater induction of PGHS-2 mRNA. Furthermore NS-398, a specific inhibitor of cyclooxygenase-2, blocked > 80% of the cyclooxygenase activity in TPA-treated astrocytes. These findings indicate that increased expression of PGHS-2 contributes to prostaglandin production in cultured astrocytes exposed to cytokines and other factors.
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PMID:Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures. 863 79

The human neuroblastoma cell line NB-39-nu expressed mRNA coding for inducible nitric oxide synthase (iNOS) following treatment with a combination of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). The level of iNOS mRNA peaked 24 h after stimulation and had declined by about 25% after 48 h. Trace levels of iNOS mRNA were detected after treatment with IFN-gamma alone, and its mRNA level was synergistically enhanced by simultaneous treatment with TNF-alpha. Neither bacterial lipopolysaccharide nor interleukin-1 beta (IL-1 beta) showed synergistic effects as great as that of TNF-alpha on iNOS gene expression. Dexamethasone inhibited the induction of iNOS mRNA by IFN-gamma and TNF-alpha. Induction of iNOS was confirmed by NADPH-diaphorase staining and by immunostaining with human iNOS-specific antibody.
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PMID:Nitric oxide synthase expression in human neuroblastoma cell line induced by cytokines. 872 59


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