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)

The effect of calmodulin inhibitors on synoviocyte phospholipase A2 activity was evaluated. Cells were incubated with [3H]arachidonic acid after 24 hours to label phospholipids. [3H]prostaglandin E2 synthesis was stimulated by Salmonella minnesota lipopolysaccharide (100 micrograms/ml). Trifluoperazine, 35 microM, reduced lipopolysaccharide-stimulated [3H]prostaglandin E2 synthesis by 50%. In sonicated suspensions of cells, calcium-dependent phospholipase A2 activity was inhibited by trifluoperazine 3-100 microM and by compound 48/80 (3 micrograms/ml). These agents inhibit calmodulin-dependent enzyme activity. The addition of calmodulin, 1 or 2.5 microM, to compound 48/80-treated suspensions reversed this inhibition in a dose-dependent manner. Agents which inhibit calmodulin-dependent enzymes can reversibly inhibit synoviocyte phospholipase A2 and thus prostaglandin E2 production.
 ...
PMID:Effects of calmodulin inhibitors on rabbit synoviocyte phospholipase A2. 311 95

E. coli lipopolysaccharide (LPS) stimulated a dose- and time-dependent release of prostaglandin E2 (PGE2) in cultured rat glomerular mesangial cells. Pertussis toxin, an inhibitor of several GTP-binding proteins (G proteins), blocked nearly 80% of the LPS-stimulated PGE2 formation, while having virtually no effect on calcium ionophore-stimulated PGE2 production. We tested the possibility that a G protein-coupled activation of phospholipase A2 mediated the LPS-stimulated PGE2 production. Evidence for LPS activation of phospholipase A2 included a time-dependent LPS-induced generation of [32P]lysophosphatidylcholine and the inhibitory effects of a phospholipase A2 inhibitor, mepacrine, on LPS-induced PGE2 formation. Possible roles for phospholipase C-dependent activation of PGE2 synthesis by LPS seemed unlikely, as LPS did not elevate the cytosolic free calcium concentration or augment the appearance of water-soluble inositol phosphates. We conclude that LPS-induced PGE2 synthesis in rat glomerular mesangial cells is mediated through a G-protein-coupled phospholipase A2 activation. The activation of phospholipase A2 releases arachidonic acid and stimulates PGE2 synthesis preferentially, thereby improving glomerular hemodynamic events in endotoxemia.
 ...
PMID:Involvement of a pertussis toxin-sensitive G-protein-coupled phospholipase A2 in lipopolysaccharide-stimulated prostaglandin E2 synthesis in cultured rat mesangial cells. 314 15

The problem of whether human pancreatic phospholipase A2 (PLA2) can really hydrolyze membrane phospholipids in vitro was studied to understand pathophysiology of acute pancreatitis. Total amount of lysophospholipids generated in erythrocytes by exogenously added human pancreatic PLA2 (2 micrograms/ml) was only 12% of the amount of sphingomyelin, which was not decomposed by the enzyme. About fivefold the amount of lysophospholipids was generated in ghost membranes during one-sixth of the incubation time compared to that in intact erythrocyte membranes. Escherichia coli lipopolysaccharide (LPS) (10 micrograms/ml) was able to stimulate membrane-associated PLA2 of erythrocytes, the amount of lysophospholipids generated being 12.5% of that of sphingomyelin without adding the exogenous PLA2. The stimulation of membrane-associated PLA2 in erythrocytes was inhibited by pretreatment of lipopolysaccharide with polymyxin-B sulfate. When intact erythrocytes were incubated with human pancreatic PLA2 and LPS, the amount of generated lysophospholipids was 24% of that of sphingomyelin. These results suggested that the exogenously added human pancreatic PLA2 cannot degrade phospholipids of intact erythrocytes so extensively under physiological conditions, and, in acute pancreatitis, unknown factors may be involved in the hydrolysis of phospholipids. LPS, which activates membrane-associated PLA2, may be one of the factors, and thus membrane phospholipids are hydrolyzed in the disease.
 ...
PMID:Hydrolytic activities of human pancreatic phospholipase A2 and endotoxin-stimulated endogenous phospholipase A2 toward membrane phospholipids of erythrocytes. 388 99

The release of prostaglandin E2 (PGE2) from cortical slices of mice into incubation medium is followed for 3 h and compared to PGE2 levels in the corresponding slice. Immediately after decapitation, the rate of PGE2 released into the incubation medium is elevated and a steady low rate of spontaneous release is gained within 1-2 h of incubation. PGE2 synthesis and release is blocked in a dose-dependent manner by either indomethacin (3 X 10(-6) -3 X 10(-4) M) or flufenamic acid (2.6 X 10(-6) M) either when added in vitro or administered in vivo. Full recovery of PGE2 synthesis is reached after 3 h incubation of slices following in vivo administration of indomethacin. In vivo administration of flufenamic acid results in prolonged inhibition of PGE2 released in vitro. The inhibition of PGE2 released by indomethacin is also correlated with the slice PGE2 content. Administration of lipopolysaccharide (LPS), a known activator of phospholipase A2, results in a fivefold increase in PGE2 and a twofold increase in 6-keto-PGF1 alpha released into the medium. The release of thromboxane B2 is not affected by LPS.
 ...
PMID:An ex vivo method for evaluating prostaglandin synthetase activity in cortical slices of mouse brain. 392 56

A protein resembling calmodulin was isolated from non-parenchymal and parenchymal cells of rat liver by affinity chromatography. The biological activity of the purified protein was assessed by the bovine brain cAMP phosphodiesterase assay. A highly sensitive radioimmunoassay as well as the cAMP phosphodiesterase method were employed to determine the calmodulin content of crude extracts from monolayer cultures of rat Kupffer cells and hepatocytes. An ATP-dependent, calmodulin-enhanced calcium transport was demonstrated in a membrane fraction of the non-parenchymal cells. Phospholipase A2 activity specific for 2-arachidonoyl phosphatide and with a pH optimum of 8.1 was measured in homogenized Kupffer cells; it was stimulated by agents previously shown to enhance prostaglandin synthesis in Kupffer cells, e.g. zymosan particles and lipopolysaccharide isolated from Salmonella minnesota. The increase in activity was completely prevented by pretreatment with or simultaneous addition of R 24571, a known calmodulin antagonist. However, if this inhibitor or calmodulin was added to the cell-free extract phospholipase A2 activity was not influenced. Phospholipase A1 activity could be detected at pH 5 only, showing a slight decrease in the homogenate of stimulated macrophages. Acyltransferase activity was high but independent of treatment of the Kupffer cells.
 ...
PMID:Calmodulin content and activity of Ca2+-ATPase and phospholipase A2 in rat Kupffer cells. 623 Nov 83

The secretion of the phospholipase A2-inhibitor macrocortin and the binding of dexamethasone were studied in suspensions of rat peritoneal macrophages. Corticosteroid-induced macrocortin secretion was specific for glucocorticoids and did not occur in response to glucocorticoid antagonists or other steroids or in response to non-steroid macrophage activators (formyl-methionyl-leucyl-phenylalanine f-MLP), the calcium ionophore A23187, phorbol myristate acetate (PMA) and lipopolysaccharide-E.-coli(LPS) ). The apparent potency of competition by secretory glucocorticoids for dexamethasone binding to the macrophage parallelled their ability to induce secretion, implying that these binding sites represent the receptors by which macrocortin secretion is initiated. Agents which interfere with microtubule assembly (colchicine, vinblastine and trimethylcolchicinic acid) and prostacyclin and dibutyryl cyclic AMP inhibit macrocortin secretion. Inhibition studies of glucocorticoid-induced macrocortin secretion also suggest dependence upon metabolic energy, a source of Ca2+ and proteolysis and glycosylation prior to secretion.
 ...
PMID:Specificity and inhibition of glucocorticoid-induced macrocortin secretion from rat peritoneal macrophages. 631 16

The synthesis and secretion of prostaglandins and leukotrienes by mouse peritoneal macrophages is under several regulatory controls. Arachidonic acid must first be released from phospholipid stores by the action of phospholipases. Macrophages have the capacity to deacylate arachidonic acid directly from the SN2 position of phospholipids via the action of a phospholipase A2. In addition, these cells contain a phospholipase C capable of removing inositol-phosphate from phosphatidylinositol generating diacylglycerol. Another enzyme, diacylglycerol lipase is present to then generate arachidonic acid. The free arachidonic acid then enters the cyclooxygenase pathway to generate prostaglandins, the lipoxygenase pathway to generate leukotrienes or both pathways. The nature of the inflammatory stimulus added to these cells determines which of the above pathways become operative. Zymosan and the Ca++ ionophore, A23187 stimulate the synthesis of both prostaglandins and leukotrienes whereas phorbol myristate acetate and lipopolysaccharide induce only the synthesis of prostaglandins. In addition, the synthesis of these two products by macrophages can be regulated by certain antiinflammatory compounds. Indomethacin, aspirin, ibuprofen and benoxaprofen are only inhibitors of the prostaglandin pathway, whereas BW755C, 5,8,11-ETYA, NDGA and sulindac sulfide (high doses) are inhibitors of the synthesis of both prostaglandins and leukotrienes. Dapsone, an effective drug for leprosy, also inhibits the synthesis of both of these products.
 ...
PMID:Physiological and pharmacological regulation of prostaglandin and leukotriene production by macrophages. 632

Previous studies have demonstrated that exposure of guinea pig macrophages to a primary signal, such as lipopolysaccharide (LPS), stimulates the synthesis of prostaglandin E2 (PGE2) which, in turn, elevates cAMP levels resulting in the production of the enzyme, collagenase. The potential of regulating the biochemical events in this activation sequence was examined with the anti-inflammatory agents dexamethasone and colchicine, which suppress the destructive sequelae in chronic inflammatory lesions associated with the degradation of connective tissue. The addition of dexamethasone with LPS to macrophage cultures resulted in a dose-dependent inhibition of PGE2 and collagenase production, which was reversed by the exogenous addition of phospholipase A2. Collagenase production was also restored in dexamethasone-treated cultures by the addition of products normally produced as a result of phospholipase action, such as arachidonic acid, PGE2 or dibutyryl-cAMP. Since the effect of dexamethasone was thus linked to phospholipase A2 inhibition, mepacrine, a phospholipase inhibitor, was also tested. Mepacrine, like dexamethasone, caused a dose-dependent inhibition of PGE2 and collagenase. In addition to corticosteroid inhibition, colchicine was also found to block collagenase production. However, this anti-inflammatory agent had no effect on PGE2 synthesis. Colchicine was effective only when added at the onset of culture and not 24 h later, implicating a role for microtubules in the transmission of the activation signal rather than enzyme secretion. The failure of lumicolchicine to inhibit collagenase activity provided additional evidence that microtubules are involved in the activation of macrophages. These findings demonstrate that dexamethasone and colchicine act at specific steps in the activation sequence of guinea pig macrophages to regulate collagenase production.
 ...
PMID:Regulation of guinea pig macrophage collagenase production by dexamethasone and colchicine. 632 92

The effect of aniso-osmotic exposure on the level of inducible cyclooxygenase (Cox-2) and on prostanoid synthesis was studied in cultured rat liver macrophages (Kupffer cells). In lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate-stimulated Kupffer cells, hyperosmotic (355 mosmol/l) exposure, due to addition of NaCl or impermeant sugars, markedly increased prostaglandin (PG) E2, D2 and thromboxane B2 synthesis in a time- and osmolarity-dependent manner. Increased prostanoid production was observed about 8 h after exposure to LPS in hyperosmotic medium compared to Kupffer cells treated with LPS under normotonic (305 mosmol/l) conditions. A similar stimulatory effect of hyperosmolarity on PGE2 production was also seen when arachidonate was added exogenously. Hyperosmotic stimulation of PGE2 production was accompanied by a strong induction of Cox-2 mRNA levels and an increase in immunoreactive Cox-2, whereas the levels of immunoreactive phospholipase A2 and cyclooxygenase-1 did not change significantly. Dexamethasone, indomethacin and the selective Cox-2 inhibitor, NS-398, abolished the hypertonicity-induced stimulation of PGE2 formation; dexamethasone also prevented the increase in Cox-2 mRNA and protein. The increase of immunoreactive Cox-2 lasted for about 24 h and was also blocked by actinomycin D or cycloheximide, but not by brefeldin A. Tunicamycin or treatment with endoglucosidase H reduced the molecular mass of hypertonicity-induced Cox-2 by 5 kDa. Tunicamycin treatment also suppressed the hypertonicity-induced stimulation of PGE2 production. The hyperosmolarity/LPS-induced stimulation of prostaglandin formation was partly sensitive to protein kinase C inhibition but was not accompanied by an increase in the cytosolic free Ca2+ concentration. The data suggest that osmolarity may be a critical factor in the regulation of Cox-2 expression and prostanoid production in activated rat liver macrophages.
 ...
PMID:Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages. 749 3

Prostaglandin E2 is observed at elevated levels during human immunodeficiency virus (HIV) infection and thus may contribute to the HIV-dependent immunosuppression. The mechanisms responsible for this increase are not understood. Evidence indicates that the viral envelope proteins perturb membrane signaling mediated by the CD4 receptor, suggesting that the free envelope protein and/or the intact virus may be responsible for the increase in prostaglandin E2 levels. In this study, we have used THP-1 human monocytes and THP-1 cells differentiated by 12-O-tetradecanoylphorbol-13-acetate treatment into macrophages to determine if the HIV envelope protein, gp120, or an anti-CD4 receptor antibody stimulates prostaglandin formation by interacting with the CD4 receptor. Incubation of THP-1 cells with OKT4A antibody greatly stimulated the CD4-p56lck receptor complex as estimated by enhanced p56lck autophosphorylation, while the gp120 gave small but significant responses. Monocytic THP-1 cells poorly metabolized arachidonic acid to prostaglandin E2 and thromboxane B2 as measured by high-pressure liquid chromatography analysis. Western blot (immunoblot) and Northern (RNA) blot analyses revealed that unstimulated monocytes expressed little prostaglandin H synthase 1 and 2 (PGHS-1 and -2). Incubation of the monocytes with lipopolysaccharide, OKT4A, or gp120 did not increase the formation of prostaglandins. The expression of PGHS-1 or PGHS-2 was also not increased. Differentiation of the monocytes to macrophages by 12-O-tetradecanoylphorbol-13-acetate treatment resulted in increased expression of PGHS-1 and increased formation of prostaglandins compared with that for the monocytes. Lipopolysaccharide stimulation of the macrophages increased the formation of prostaglandins and increased the expression of PGHS-2 in the macrophages. However, OKT4A or gp120 preparation, at concentrations that stimulated p56lck autophosphorylation, did not enhance the formation of prostaglandins or the expression of PGHS-1 or PGHS-2. OKT4A and gp120 also did not stimulate the release of arachidonic acid, indicating that phospholipase A2 was not activated by the CD4 receptor in either the THP-1 monocytes or macrophages. These results indicate that activation of the CD4-p56lck receptor signal transduction pathway by the HIV envelope protein does not increase prostaglandin formation.
 ...
PMID:Human immunodeficiency virus type 1 envelope protein does not stimulate either prostaglandin formation or the expression of prostaglandin H synthase in THP-1 human monocytes/macrophages. 749 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>