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 two cyclooxygenase isoforms, cyclooxygenase-1 and cyclooxygenase-2, both metabolize arachidonic acid to prostaglandin H2, which is subsequently processed by downstream enzymes to the various prostanoids. In the present study, we asked if the two isoforms differ in the profile of prostanoids that ultimately arise from their action on arachidonic acid. Resident peritoneal macrophages contained only cyclooxygenase-1 and synthesized (from either endogenous or exogenous arachidonic acid) a balance of four major prostanoids: prostacyclin, thromboxane A2, prostaglandin D2, and 12-hydroxyheptadecatrienoic acid. Prostaglandin E2 was a minor fifth product, although these cells efficiently converted exogenous prostaglandin H2 to prostaglandin E2. By contrast, induction of cyclooxygenase-2 with lipopol- ysaccharide resulted in the preferential production of prostacyclin and prostaglandin E2. This shift in product profile was accentuated if cyclooxygenase-1 was permanently inactivated with aspirin before cyclooxygenase-2 induction. The conversion of exogenous prostaglandin H2 to prostaglandin E2 was only modestly increased by lipopolysaccharide treatment. Thus, cyclooxygenase-2 induction leads to a shift in arachidonic acid metabolism from the production of several prostanoids with diverse effects as mediated by cyclooxygenase-1 to the preferential synthesis of two prostanoids, prostacyclin and prostaglandin E2, which evoke common effects at the cellular level.
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PMID:Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. 1020 78

A novel murine model of intrauterine infection/inflammation-induced preterm birth based on direct endoscopic intracervical inoculation is described. Using this model, we investigated infection-induced premature pregnancy loss in normal and interleukin (IL) 1beta-deficient mice. Seventy-four CD-1, HS, C57BL/6J wild type (IL-1beta+/+), and C57BL/6J IL-1beta-deficient (IL-1beta-/-) mice were inoculated intracervically using a micro-endoscope, at a time corresponding to 70% of average gestation. Intracervical injection of lipopolysaccharide (LPS) or Escherichia coli reliably induced premature birth: 100% of mice intracervically injected with LPS and 92% of mice with a positive endometrial E. coli culture delivered prematurely within 36 h after inoculation. No losses were observed in mice inoculated with saline. Pregnancy loss was associated with increased uterine tissue cyclooxygenase-2 gene expression and uterine content of IL-1beta, tumor necrosis factor alpha, macrophage inflammatory protein-1alpha, and IL-6, as well as elevation of nuclear factor-kappaB activity in uterine tissues. Although IL-1beta-/- mice exhibited decreased uterine cytokine production in response to bacteria and LPS, IL-1beta deficiency did not affect the rate of pregnancy loss. This model using direct intracervical bacterial or LPS inoculation is useful for studying preterm pregnancy loss in genetically altered mice in order to develop novel interventions for infection-associated preterm labor.
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PMID:Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: role of interleukin 1beta. 1020 89

Group V secretory phospholipase A2 (sPLA2) rather than Group IIA sPLA2 is involved in short term, immediate arachidonic acid mobilization and prostaglandin E2 (PGE2) production in the macrophage-like cell line P388D1. When a new clone of these cells, P388D1/MAB, selected on the basis of high responsivity to lipopolysaccharide plus platelet-activating factor, was studied, delayed PGE2 production (6-24 h) in response to lipopolysaccharide alone occurred in parallel with the induction of Group V sPLA2 and cyclooxygenase-2 (COX-2). No changes in the level of cytosolic phospholipase A2 (cPLA2) or COX-1 were observed, and Group IIA sPLA2 was not detectable. Use of a potent and selective sPLA2 inhibitor, 3-(3-acetamide 1-benzyl-2-ethylindolyl-5-oxy)propanesulfonic acid (LY311727), and an antisense oligonucleotide specific for Group V sPLA2 revealed that delayed PGE2 was largely dependent on the induction of Group V sPLA2. Also, COX-2, not COX-1, was found to mediate delayed PGE2 production because the response was completely blocked by the specific COX-2 inhibitor NS-398. Delayed PGE2 production and Group V sPLA2 expression were also found to be blunted by the inhibitor methylarachidonyl fluorophosphonate. Because inhibition of Ca2+-independent PLA2 by an antisense technique did not have any effect on the arachidonic acid release, the data using methylarachidonyl fluorophosphonate suggest a key role for the cPLA2 in the response as well. Collectively, the results suggest a model whereby cPLA2 activation regulates Group V sPLA2 expression, which in turn is responsible for delayed PGE2 production via COX-2.
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PMID:Regulation of delayed prostaglandin production in activated P388D1 macrophages by group IV cytosolic and group V secretory phospholipase A2s. 1021 94

Various lines of evidence have implicated inducible cyclooxygenase-2 (COX-2) in fever production. Thus, its expression is selectively enhanced in brain after peripheral exogenous (e.g., lipopolysaccharide [LPS]) or endogenous (e.g., interleukin-1) pyrogen administration, while selective COX-2 inhibitors suppress the fever induced by these pyrogens. In this study, we assessed the febrile response to LPS of congenitally constitutive COX-1 (COX-1-/-) and COX-2 (COX-2-/-)-deficient C57BL/6J-derived mice. COX-1+/- and COX-2+/- mice were also evaluated; controls were wild-type C57BL/6J mice (Jackson Labs.). All the animals were pretrained daily for two weeks to the experimental procedures. LPS was injected intraperitoneally at 1 microgram/mouse; pyrogen-free saline (PFS) was the vehicle and control solution. Core temperatures (Tcs) were recorded using thermocouples inserted 2 cm into the colon. The presence of the COX isoforms was determined in cerebral blood vessels immunocytochemically after the experiments, without knowledge of the functional results. The data showed that the wild-type, COX-1+/-, and COX-1-/- mice all responded to LPS with a 1 degrees C rise in Tc within 1 h; the fever gradually abated over the next 4 h. By contrast, COX-2+/- and COX-2-/- mice displayed no Tc rise after LPS. PFS did not affect the Tc of any animal. It would appear therefore that COX-2 is necessary for LPS-induced fever production.
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PMID:The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice. 1021 76

In a previous work, we tested a series of chalcone derivatives as possible anti-inflammatory compounds. We now investigate the effects of three of those compounds, CHI, CH8 and CH12, on nitric oxide and prostanoid generation in mouse peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air pouch injected with zymosan, where they showed a dose-dependent inhibition with inhibitory concentration 50% values in the microM range. This effect was not the consequence of a direct inhibitory action on enzyme activities. Our results demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide synthase and cyclooxygenase-2 synthesis, being a novel therapeutic approach for inflammatory diseases.
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PMID:Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages. 1040 89

There is mounting evidence that inflammatory processes, including activation of microglia, are upregulated in Alzheimer's disease. The importance of this phenomenon is indicated by multiple epidemiological studies showing that patients taking non-steroidal anti-inflammatory drugs (NSAIDs) have a substantially reduced prevalence of Alzheimer's disease. The pharmacological actions of anti-inflammatory drugs in brain are still uncertain. As a step towards identifying key pharmacological targets, we developed a neurotoxicity assay based on the property of supernatant media from stimulated human monocytic THP-1 cells to cause human neuroblastoma cell death. Similar neurotoxicity was observed when postmortem human microglia were substituted for THP-1 cells, establishing the validity of the assay for simulating neurotoxicity in human brain. A combination of lipopolysaccharide and interferon-gamma was used to activate the THP-1 cells. NSAIDs were effective in inhibiting neurotoxicity by this assay, while steroidal anti-inflammatories and propentofylline had no effect. The neuroprotective potency of NSAIDs appeared to be unrelated to their selective ability to inhibit cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). It is suggested that inhibition of monocyte cytotoxicity might be responsible for the apparent beneficial effects of NSAIDs in Alzheimer's disease.
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PMID:Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs). 1042 20

The effects of tyrphostin AG-556 (TYR), a tyrosine kinase inhibitor, were evaluated on shock induced by lipopolysaccharide (LPS) or group B streptococcus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F1alpha (6-keto PGF1alpha) was also measured at four hours after LPS injection. The effects of TYR on the production of 6-keto PGF1alpha thromboxane B2(TXB2) and nitrite (NO) from LPS or GBS stimulated in vitro peritoneal rat macrophage were also examined. Salmonella enteritidis LPS (12 mg/kg, i.v. ) (n=6) produced severe shock (100% mortality). Simultaneous treatment with TYR (n=6) significantly (p < 0.01) extended mean survival time and 33% of rats survived. Plasma 6-keto PGF1alpha concentrations were increased in LPS controls, whereas TYR (5 mg/kg) significantly (p < 0.05) decreased the production. Animals treated with GBS/D-galactosamine (n=9) also exhibited shock with 100% lethality and TYR again prolonged survival time (p < 0.05) with 55% of the animals surviving. To evaluate direct effects of TYR on mediator production induced by LPS or GBS, rat macrophages were stimulated with heat-killed GBS or LPS with or without TYR. Supernatants were collected at 24 h for determination of TXB2, 6-keto PGF1alpha and NO. All mediators measured were significantly increased (p < 0.05) with LPS or GBS. TYR inhibited (p < 0.05) the production of all mediators from macrophages induced by LPS or GBS. The decrease in eicosanoids was associated with a reduction of the content of cyclooxygenase-2 (COX-2) as determined by western blotting. Collectively, these results suggest that TYR ameliorates toxic shock induced by LPS or gram positive bacteria. This protection is associated with suppression of macrophage mediator production.
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PMID:Protective effect of tyrphostin AG-556 on shock induced by endotoxin or gram positive bacteria. 1044 90

Interleukin-6 (IL-6) is a proinflammatory cytokine that plays multiple roles in the central nervous system during infections and injuries. Although this molecule is capable of stimulating the release of ACTH and glucocorticoids, it has been demonstrated that a single injection of IL-6 fails to activate the paraventricular nucleus (PVN) neurons that control the hypothalamic-pituitary-adrenal axis. The observation that IL-6 receptor (IL-6R) is up-regulated in the brain during endotoxemia led us to hypothesize that prior induction of IL-6R synthesis could amplify the effect of circulating IL-6 on the neuroendocrine response. Rats received a first iv injection of either bacterial lipopolysaccharide (LPS; 5 microg) or vehicle solution. After a 6-h waiting period, they received a second iv injection of either recombinant rat IL-6 or vehicle solution and were killed 1 h thereafter. Using in situ hybridization, we observed that IL-6R was barely expressed in the PVN under basal conditions, but was rapidly produced in response to LPS. IL-6 itself was also able to induce the synthesis of its own receptor along cerebral blood vessels, and this effect extended to several parenchymal structures, including the PVN, when the cytokine was administrated after LPS. In agreement with our hypothesis, we found that IL-6 injected in LPS-pretreated rats stimulated PVN neurons, as revealed by the expression of CRF primary transcript and c-fos messenger RNA, an immediate early gene used as a marker of cellular activation. A significant increase in plasma corticosterone levels was also found in animals that received iv IL-6 injection after being pretreated 6 h before with the very low dose of LPS. The fact that IL-6 alone or injected after LPS treatment was unable to induce cyclooxygenase-2 synthesis is an argument in favor of a PG-independent mechanism. The relative contribution of IL-6 in stimulating CRF expression in the PVN and neural activity throughout the brain during endotoxemia was also investigated in IL-6-deficient mice after an ip injection of LPS. The endotoxin induced similar c-fos and CRF expression patterns in knockout and wild-type mice, but the expression levels were generally higher and/or lasted longer in wild-type animals. Taken together, physiological changes that may include the induction of IL-6R synthesis seem to be necessary for IL-6 to activate PVN neurons. Moreover, although IL-6 does not appear essential during the early phases of endotoxemia, this cytokine is required during the later phases to prolong the activation of neural cells throughout the brain and to maintain CRF expression in the PVN neurons that control the hypothalamic-pituitary-adrenal axis.
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PMID:Interleukin-6 is a needed proinflammatory cytokine in the prolonged neural activity and transcriptional activation of corticotropin-releasing factor during endotoxemia. 1046 57

When exposed for prolonged periods of time (up to 20 h) to bacterial lipopolysaccharide (LPS) murine P388D(1) macrophages exhibit a delayed prostaglandin biosynthetic response that is entirely mediated by cyclooxygenase-2 (COX-2). Both the constitutive Group IV cytosolic phospholipase A(2) (cPLA(2)) and the inducible Group V secretory phospholipase A(2) (sPLA(2)) are involved in the cyclooxygenase-2-dependent generation of prostaglandins in response to LPS. Using the selective sPLA(2) inhibitor 3-(3-acetamide-1-benzyl-2-ethylindolyl-5-oxy)propane sulfonic acid (LY311727) and an antisense oligonucleotide specific for Group V sPLA(2), we found that induction of COX-2 expression is strikingly dependent on Group V sPLA(2), which was further confirmed by experiments in which exogenous Group V sPLA(2) was added to the cells. Exogenous Group V sPLA(2) was able to induce significant arachidonate mobilization on its own and to induce expression of the COX-2. None of these effects was observed if inactive Group V sPLA(2) was utilized, implying that enzyme activity is crucial for these effects to take place. Therefore, not only delayed prostaglandin production but also COX-2 gene induction are dependent on a catalytically active Group V sPLA(2). COX-2 expression was also found to be blunted by the Group IV cPLA(2) inhibitor methyl arachidonyl fluorophosphonate, which we have previously found to block Group V sPLA(2) induction as well. Collectively, the results support a model whereby Group IV cPLA(2) activation regulates the expression of Group V sPLA(2), which in turn is responsible for delayed prostaglandin production by regulating COX-2 expression.
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PMID:Group V phospholipase A(2)-dependent induction of cyclooxygenase-2 in macrophages. 1047 37

Bovine aortic endothelial cells produce prostacyclin as their major arachidonic acid metabolite. cAMP, in turn, is the second messenger for prostacyclin. In the present study, we investigated the effects of cAMP-elevating agents on prostacyclin production by bovine aortic endothelial cells. Treatment of resting bovine aortic endothelial cells with cAMP-elevating agents inhibited prostacyclin production and cyclooxygenase activity, without affecting arachidonic acid release. No change was detected in cyclooxygenase-1 protein expression. The specific inhibitor of protein kinase A, Rp-cAMPS (adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, triethylammonium salt), and the phosphatase inhibitor, okadaic acid, both suppressed cAMP-induced inhibition, suggesting that this inhibition is mediated by a phosphorylation-dephosphorylation cascade, which is possibly protein kinase A-dependent. In lipopolysaccharide-treated cyclooxygenase-2 expressing bovine aortic endothelial cells, where cyclooxygenase-1 activity was selectively inhibited, dibutyryl cAMP failed to inhibit cyclooxygenase-2 activity. Cyclooxygenase-2 protein was induced upon treatment with dibutyryl cAMP and further induction of cyclooxygenase-2 protein was effected by IBMX (3-isobutyl-1-methyl-xanthine) and dibutyryl cAMP in bacterial lipopolysaccharide-stimulated cells. These results suggest that increased cellular cAMP selectively inhibits cyclooxygenase-1 activity without altering cyclooxygenase-1 protein expression, and at the same time, up-regulates cyclooxygenase-2 protein. This complex regulation of cyclooxygenase activity and protein expression by cAMP may represent a prostacyclin-induced autoregulatory mechanism in bovine aortic endothelial cells.
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PMID:Differential regulation of cyclooxygenase isoenzymes by cAMP-elevating agents. 1047 33


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