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)

Stimulation of mouse RAW 264.7 macrophages with UTP activates both the inositol phosphate signal transduction pathway and the phospholipase A2 pathway. In the present study, we investigated the interactions between bacterial lipopolysaccharide and UTP in these two systems and the underlying mechanisms involved. While the UTP-induced release of arachidonic acid was only 2.9-fold that in controls, priming the cells with 1 microgram/ml lipopolysaccharide for 1 h before UTP treatment resulted in 9.2-fold arachidonic acid release upon stimulation with UTP. Lipopolysaccharide priming was both concentration- and time-dependent with a peak effect after 1 h treatment at a concentration of 1 microgram/ml. Lipopolysaccharide treatment affect neither the basal nor the UTP-stimulated inositol phosphate formation and [Ca2+]i rise. Pretreatment of the cells with staurosporine, calphostin, N-(2-aminoethyl)-5-isoquinolinesulfonamide H-7), genistein or K-252a led marked inhibition of the priming effect, suggesting that both protein kinase C and tyrosine kinase are involved in the lipopolysaccharide effect. Buffering intracellular Ca2+ levels using [1,2-bis-(o-aminophenoxyl)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester] (BAPTA/AM) or pretreatment with either N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H-89), 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD098059) or {1-N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl] -4-phenyl-piperazine (KN-62) did not affect the lipopolysaccharide-induced priming effect. Primed UTP stimulation was inhibited by actinomycin D and cycloheximide, indicating a requirement for both gene expression and protein translation. To further examine whether the stimulatory effects of lipopolysaccharide on phospholipase A2 activity were independent of [Ca2+]i levels but dependent on protein phosphorylation, a fixed Ca2+ concentration and inhibitors of protein phosphatases were used in primed permeabilized cells. Arachidonic acid release from permeabilized cells containing 100 nM Ca2+ was high in lipopolysaccharide-primed cells and potentiated by addition of microcystin, orthovanadate or FK 506. These results that the Ser/Thr and tyrosine phosphorylation cascades induced by protein kinase C and tyrosine kinase, respectively, are required for the arachidonic acid potentiation effect of lipopolysaccharide, which was independent of modulation of the upper stream signaling pathways of UTP.
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PMID:Priming effects of lipopolysaccharide on UTP-induced arachidonic acid release in RAW 264.7 macrophages. 908 94

The interference of the 5-lipoxygenase inhibitor, BW B70C ((E)-N-(3-[3-(4-fluorophenoxy)phenyl]-1(R,S)-methyl prop-2-enyl)-N-hydroxyurea), with Escherichia coli lipopolysaccharide (endotoxin)-induced lung leucocyte sequestration and microvascular albumin exchanges was evaluated in the anaesthetised guinea-pig using radioactive tracers, in parallel to the effects on cell counts in the broncho-alveolar lavage fluid, blood tumour necrosis factor (TNF-alpha) content, secretion of phospholipase A2 and synthesis of leukotriene C4 by alveolar macrophages. Intravenous injections of 0.1 or 1 mg/kg endotoxin induced lung leucocyte sequestration but only the higher dose induced an increase in albumin microvascular exchanges and the infiltration of leucocytes towards the airway lumen. Leukotriene B4, a potential mediator of the 5-lipoxygenase-dependent endotoxin effects, induced a rapid and transient lung leucocyte sequestration and leucopenia associated with a more progressive increase in microvascular exchanges. The 5-lipoxygenase inhibitor, BW B70C, injected i.p. (30 mg/kg) prevented leukotriene C4 synthesis by alveolar macrophages and reduced leucocyte migration to the airways lumen as well as albumin microvascular leakage but did not affect the endotoxin-induced increase in the blood level of TNF-alpha and of secreted phospholipase A2. However, BW B70C failed to modify vascular leucocyte margination induced by 1 mg/kg endotoxin, suggesting that, apart from a role of 5-lipoxygenase, alternative pathways operate in response to endotoxin in guinea-pig.
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PMID:5-Lipoxygenase and endotoxin-induced microvascular albumin exchanges and leucocyte recruitment in guinea-pig lungs. 913 18

To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 +/- 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-alpha2-antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-alpha1-antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P > .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.
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PMID:Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. 916 Jun 78

To define the isoform of phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A2. We found that inhibitors of cytosolic phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A2 had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) beta2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1beta, which further enhances cytosolic phospholipase A2 activity and expression. Thus, superinduction of cytosolic phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A2 but not secretory phospholipase A2 is the predominant enzyme in inflammatory signalling.
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PMID:Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A2. 919 77

Infection with Helicobacter pylori (H. pylori) is now recognized as a major factor in the pathogenesis of gastric disease, and the successful therapy regimens require a combination of H2 blockers with gastroprotective and antimicrobial agents. Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene) amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) is the only drug combining acid-suppressant activity with remarkable gastroprotective and anti-H. pylori properties. The drug not only displays a potent anti-H. pylori activity alone, but also exerts a strong potentiating effect on the efficacy of antimicrobial agents commonly used for H. pylori eradication, and the successful ulcer therapy with ebrotidine induces a significant (4-fold) increase in the H. pylori aggregation titer of gastric mucin. Moreover, the drug exhibits a strong inhibitory effect on H. pylori urease activity, the extent of which exceeds that of ranitidine, omeprazole and lansoprazole. Ebrotidine has also been demonstrated to exert a potent inhibitory action on the enzymatic activities directed towards mucus perimeter of gastric mucosal defense, causing a marked inhibition of H. pylori protease, lipase and phospholipase A2 activities. Another important property of ebrotidine is its ability to efficiently counteract the disruptive effects of H. pylori lipopolysaccharide on the integrity of gastric epithelium. This includes countering the interference by the lipopolysaccharide in mucosal integrin receptor interaction with proteins of extracellular matrix and the reversal of H. pylori disruptive effect on the binding of mucin to its gastric epithelial receptor. Furthermore, most recent data indicate that ebrotidine has the ability to reverse the impairment caused by H. pylori in feedback inhibition of gastrin release by somatostatin. This activity of ebrotidine apparently stems from the drug's ability to counter the untoward effect of H. pylori on the binding of somatostatin to its specific receptor on the gastric mucosal G-cells. The unique combination of acid suppressant, gastroprotective and anti-H. pylori activities makes ebrotidine a drug of choice in the treatment of gastric disease caused by H. pylori.
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PMID:Anti-Helicobacter pylori activities of ebrotidine. A review of biochemical and animal experimental studies and data. 920 47

Portal venous transfusions (PVTs) of blood have been shown to induce significant immunosuppression in animal models of organ transplantation. A proposed mechanism of PVT-induced immunosuppression is via alteration of Kupffer cell arachidonic acid metabolism with increased secretion of the suppressive metabolite prostaglandin E2 (PGE2). This study assessed the hypothesis that PVT increases Kupffer cell PGE2 production via up-regulation of Kupffer cell phospholipase A2 (PLA2) as well as constitutive (COX1) and inducible (COX2) cyclooxygenase. Kupffer cells from Lewis rats were harvested 1 hr after PVT with either 1 ml of Wistar-Furth blood, systemic transfusion (SVT), or saline via portal vein (PVSal). After lipopolysaccharide stimulation, 24-hr Kupffer cell supernatant fractions were assayed for PGE2. PGE2 was increased after SVT (1465+/-234 pg/ml) compared with PVSal (597+/-99; P<0.01). PVT increased Kupffer cell PGE2 (5370+/-533; P<0.001 vs. SVT and vs. PVSal) even more substantially. Kupffer cells from PVT-treated rats were then cultured in the presence of inhibitors of PLA2, COX1, or COX2. When Kupffer cells were treated with mepacrine to inhibit PLA2 (5575+/-453 pg/ml), PGE2 production was not different from that by PVSal-treated controls (6467+/-614 pg/ml), but when Kupffer cells were incubated in the presence of the COX1 inhibitor flurbiprofen (3512+/-407 pg/ml) or the COX2 inhibitor nimesulide (2800+/-830 pg/ml), production was decreased 46.7% and 56.7%, respectively, over control activity without added inhibitor. PVT also increased Kupffer cells COX1 and COX2 mRNA as measured by Northern blot. Heart transplants were then performed from Wistar-Furth donors into Lewis recipients at the time of PVT, SVT, PVSal, or PVT + indomethacin (COX1/2 inhibitor). PVT prolonged allograft survival (12.0+/-0.9 days) compared with PVSal (6.3+/-0.3; P<0.01) or SVT (6.3+/-0.3; P<0.04). Indomethacin shortened graft survival when given with PVT (6.5+/-0.3 days). In summary, PVT increased Kupffer cell PGE2 production, up-regulated transcription of Kupffer cells COX1 and COX2 mRNA, and prolonged cardiac allograft survival. COX1/2 inhibition abrogated the effect of PVT. The results indicated that the immunosuppressive effect of PVT may be mediated by up-regulation of Kupffer cell COX1 and COX2. Manipulation of Kupffer cell arachidonic acid metabolism may be useful in augmentation of PVT-induced immunosuppression.
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PMID:Portal venous transfusion up-regulates Kupffer cell cyclooxygenase activity: a mechanism of immunosuppression in organ transplantation. 923 13

Ceramide has emerged as an important lipid messenger for many cellular processes triggered via surface receptors. In the present study, inflammatory activation of P388D1 macrophages with bacterial lipopolysaccharide (LPS) and platelet-activating factor (PAF) stimulated a transient accumulation of ceramide. Moreover, cell-permeable ceramide mimicked LPS/PAF in triggering arachidonate mobilization in these cells. LPS/PAF-induced ceramide synthesis did not result from sphingomyelinase activation but from increased de novo synthesis. Participation of this pathway in arachidonate signaling was detected since fumonisin B1, an inhibitor of de novo ceramide synthesis, was able to inhibit the LPS/PAF-induced response. These studies have uncovered a new role for sphingolipid metabolism in cellular signaling and constitute evidence that products of the sphingomyelin biosynthetic pathway may serve a specific role in signal transduction by influencing the activity of the novel Group V secretory phospholipase A2.
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PMID:Inflammatory activation of arachidonic acid signaling in murine P388D1 macrophages via sphingomyelin synthesis. 925 42

Sulfasalazine is widely used in rheumatoid arthritis and inflammatory bowel diseases. The mechanisms of its activity have not been elucidated. In leukocytes, sulfasalazine and its analogue, CL 42A, inhibited the formation of leukotrienes and possibly of the second messenger compounds at the level of phospholipase C. Partial inhibition of interleukin-lbeta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) was also found. Since the synthesis of eicosanoids is induced by phospholipase A2 and since secretory phospholipase A2 (sPLA2) is proinflammatory, we investigated the impact of sulfasalazine and related compounds on mRNA, protein synthesis, and release of sPLA2 from osteoblasts. Sulfasalazine and CL 42A markedly inhibited extracellular release of sPLA2. The impact of sulfasalazine was evident at 50 microM (P < 0.001) and maximal at 400 microM, and that of CL 42A at 10 microM (P < 0.001) and 200 microM, respectively. Split products of sulfasalazine, 5-aminosalicylic acid (400 microM) and sulfapyridine (400 microM), had no impact. The effect of sulfasalazine and CL 42A was evident regardless of whether the cells were stimulated with IL-1beta/TNF-alpha, lipopolysaccharide/forskolin, or dibutyryl-cAMP. Sulfasalazine and CL 42A did not alter the level of sPLA2 mRNA. Exposure of stimulated fetal rat calvaria osteoblasts (FRCO) to sulfasalazine did not show accumulation of the intracellular sPLA2 protein as tested by western blot; however, enzymatic activity of PLA2 in disrupted cells was definitely increased. Thus, the impact is on the post-transcriptional release of sPLA2 rather than on the synthesis. There was also an increase in the extracellular release of prostaglandin E2 from FRCO exposed to sulfasalazine or to CL 42A. In contrast, sulfasalazine had no effect on the extracellular release of gelatinase from the cells or on mRNA of cytosolic PLA2 or cyclooxygenase 2. We conclude that the anti-inflammatory activity of sulfasalazine may be related, in part, to the selective inhibition of the extracellular release of proinflammatory sPLA2.
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PMID:Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity. 925 65

Low intravenous doses of endotoxin [lipopolysaccharide (LPS), 0.7 microgram/kg] induce monophasic fever, increase anterior and posterior pituitary hormone release, and enhance hypothalamic c-Fos expression in pigs, all of which can be prevented by indomethacin (Ind). The present study shows that the synthetic corticosteroid dexamethasone (Dex, 5 mg/kg) has a similar action to Ind and, when given alone, lowers core temperature. In addition, the corticosteroid synthesis inhibitor metyrapone (Met, 3.3 mg/kg, every one-half hour) reduces LPS fever and amplifies the effect of LPS on vasopressin, but not on oxytocin, release. The similar actions of Dex and Ind suggest that phospholipase A2 pathways controlling prostaglandin synthesis mediate the responses of prepubertal pigs to immunological challenge with LPS. The increased vasopressin release induced when animals receiving Met are also given LPS supports findings in other nonrodent species indicating an inverse relationship between cortisol and vasopressin. The attenuation of LPS fever by Met is suggestive of an endogenous antipyretic mechanism associated with enhanced neurohypophysial vasopressin secretion.
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PMID:Interrelated adrenocortical and neurohypophysial responses associated with fever in endotoxin-treated pigs. 932 84

Mammals possess various types of secretory phospholipase A2, which differ in the primary structure and tissue distribution. The phosholipase A2 receptor (PLA2R) recognizes group IB phospholipase A2 (PLA2-IB) and mediates the PLA2-IB-induced biological responses in non-digestive organs, including eicosanoid production and contraction of airway smooth muscles. In this study, we generated PLA2R-deficient mice to define its biological roles further. These mice are viable, fertile, and without evident histopathological abnormalities. There was no difference in the clearance of circulating PLA2-IB between wild-type and mutant mice. After challenge with bacterial lipopolysaccharide (LPS), PLA2R-deficient mice exhibited longer survival than wild-type mice. The mutant mice were also resistant to lethal effects of exogenous PLA2-IB after sensitization with sublethal dose of LPS. The plasma levels of tumor necrosis factor-alpha and interleukin-1beta elevated after LPS treatment were significantly reduced in mutant mice compared with wild-type mice. These findings suggest a potential role of PLA2R in the progression of endotoxic shock.
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PMID:Resistance to endotoxic shock in phospholipase A2 receptor-deficient mice. 940 54


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