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)

Cyclooxygenase-2 (COX-2), an inducible isozyme of cyclooxygenase, is selectively expressed in response to lipopolysaccharide (LPS) and its expression is suppressed by the glucocorticoid dexamethasone (DEX) in the monocytic differentiated U937 cells. However, COX-2 mRNA was not detected nor induced by LPS before the cells differentiated. To study the transcriptional role of the NF-kappa B site (nucleotides -223 to -214) in the COX-2 gene, the luciferase reporter vector driven by the COX-2 promoter region (nucleotides -327 to +59) mutated at both the cAMP response element and the NF-IL6 site was stably transfected into U937 cells. The substantial luciferase activity observed in the undifferentiated cells was not induced by LPS. However, after the cells had differentiated, luciferase activity was induced by LPS and its induction was suppressed by DEX. Moreover, a protein tyrosine kinase inhibitor herbimycin A suppressed both the expression of COX-2 mRNA and the luciferase activity induced by LPS. These results suggest that the NF-kappa B site is involved in both the LPS-induced expression of the COX-2 gene and its suppression by DEX and herbimycin A in a differentiation-dependent manner.
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PMID:Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells. 951 89

Interleukin (IL)-1 is a major mediator of inflammation and exerts pleiotropic effects on the neuro-immuno-endocrine system. To elucidate pathophysiological roles of IL-1, we have first produced IL-1alpha/beta doubly deficient (KO) mice together with mice deficient in either the IL-1alpha, IL-1beta, or IL-1 receptor antagonist (IL-1ra) genes. These mice were born healthy, and their growth was normal except for IL-1ra KO mice, which showed growth retardation after weaning. Fever development upon injection with turpentine was suppressed in IL-1beta as well as IL-1alpha/beta KO mice, but not in IL-1alpha KO mice, whereas IL-1ra KO mice showed an elevated response. At this time, expression of IL-1beta mRNA in the diencephalon decreased 1.5-fold in IL-1alpha KO mice, whereas expression of IL-1alpha mRNA decreased >30-fold in IL-1beta KO mice, suggesting mutual induction between IL-1alpha and IL-1beta. This mutual induction was also suggested in peritoneal macrophages stimulated with lipopolysaccharide in vitro. In IL-1beta KO mice treated with turpentine, the induction of cyclooxygenase-2 (EC 1.14.99.1) in the diencephalon was suppressed, whereas it was enhanced in IL-1ra KO mice. We also found that glucocorticoid induction 8 h after turpentine treatment was suppressed in IL-1beta but not IL-1alpha KO mice. These observations suggest that IL-1beta but not IL-1alpha is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1alpha expression in the brain is dependent on IL-1beta. The importance of IL-1ra both in normal physiology and under stress is also suggested.
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PMID:Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. 956 38

Previous observations suggest expression of cyclooxygenase-2 to convey macrophage protection towards apoptotic cell death. We reasoned prostaglandin formation and in turn a cAMP increase as the underlying protective principle. Here we report that exposure of macrophages to lipopolysaccharide/interferon-gamma or lipophilic cAMP analogs such as dibutyryl-cAMP or 8-bromo-cAMP for 15 h attenuated DNA fragmentation and accumulation of the tumor suppressor p53 in response to the chemotherapeutic agents cisplatin and etoposide, compared to cells that received chemotherapeutic agents only. In contrast, a 1 h lasting preexposure period revealed no protection. The demand for a long incubation period with cAMP-derivates implied cAMP-mediated gene activation as the underlying principle. Therefore, we treated cells with oligonucleotides containing a cAMP-response element (CRE) binding site. Using this decoy-approach we scavaged activated cAMP response element binding protein prior to its promoter activating ability. Incubating macrophages with decoy, but not with control oligonucleotides, reduced cAMP evoked protection and simultaneously restored p53 accumulation in response to chemotherapeutic agents. Our studies demonstrate that cAMP-initiated gene activation regulates the sensitivity towards DNA damaging agents via inhibition of a p53 dependent pathway.
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PMID:Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMP-induced gene expression. 969 May 20

Cyclooxygenase-2 (COX-2), a key enzyme in the biosynthesis of prostaglandins, is induced in brain blood vessels by pyrogens, and its essential role in fever has been hypothesized. In this study, we determined (1) the type of cells that express cyclooxygenase-2 in brain blood vessels of lipopolysaccharide-treated rats, and (2) the precise relationship between the time course of fever and that of cyclooxygenase-2 protein expression in these cells. Five hours after the lipopolysaccharide injection (100 microg/kg, i.p.), cyclooxygenase-2-like immunoreactive cells were found in the parenchymal and subarachnoidal blood vessels. In these blood vessels, the cyclooxygenase-2-like immunoreactivity was restricted to the perinuclear region of the endothelial cells as revealed by a laser confocal microscopy, double-immunofluorescence staining with an endothelial marker, and immunoelectron microscopy. On the other hand, the cyclooxygenase-2-like immunoreactive cells were distinct from microglia or perivascular/meningeal macrophages as revealed by double immunostaining with macrophage/microglia-specific antibodies. Cyclooxygenase-2-like immunoreactive cells were first found at 1.5 hr after the lipopolysaccharide injection, at which time the fever had not been developed. After that, the number of cyclooxygenase-2-like immunoreactive cells and fever followed a similar time course, both being highest at 5 hr after the lipopolysaccharide injection and both returning to the baseline by 24 hr. These results demonstrate that brain endothelial cells are the primary sites where the activation of arachidonic acid cascade takes place during fever after intraperitoneal injection of lipopolysaccharide.
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PMID:Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies. 969 20

Pretreatment of mice with lipopolysaccharide for 16 h enhanced the number of acetic acid-induced writhing reactions by 2 to 3-fold. In the peritoneal exudates at 10 min after acetic acid injection, 6-keto-prostaglandin F1alpha was detected as a major prostanoid, and this level increased by several-fold by the pretreatment with lipopolysaccharide. The writhing reaction and the prostaglandin formation were almost completely suppressed by indomethacin. However, the lipopolysaccharide-induced enhancement of writhing reaction and an increment of 6-keto-prostaglandin F1alpha level were diminished by the administration of cyclooxygenase-2-selective inhibitors, such as NS-398, nimesulide, or L-745337, to a level similar to the mice that did not receive lipopolysaccharide. Cyclooxygenase-2 protein in the exudates became detectable at 5-48 h after the lipopolysaccharide-pretreatment. These results suggest that the increased prostaglandin production by cyclooxygenase-2 could be responsible for enhancement of the acetic acid-induced writhing reaction by lipopolysaccharide pretreatment.
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PMID:Induction of cyclooxygenase-2 causes an enhancement of writhing response in mice. 971 66

Several enzymes play a role in vasodilation, including cyclooxygenase, which converts arachidonic acid into prostaglandins, and nitric oxide synthase, which converts arginine to citrulline and yields nitric oxide. The effects of endogenous and exogenous estrogen and lipopolysaccharide on uterine artery production of prostacyclin, and levels of cyclooxygenase and nitric oxide synthase were examined. Uterine arteries collected from ewes during the follicular (Day -1 to 0, Day 0 = estrus) or luteal (Day 10) phase were treated in vitro with lipopolysaccharide. In addition, ovariectomized ewes were treated in vivo with estradiol-17beta (5 microg/kg; 120 min) or a vehicle control; arteries from the uteri were treated in vitro with lipopolysaccharide. After 24 h of lipopolysaccharide treatment, culture media were collected for measurement of 6-keto-prostaglandin F1alpha (the stable metabolite of prostacyclin). These uterine arteries were homogenized, and the level of cyclooxygenase and nitric oxide synthase was determined by Western analysis. Lipopolysaccharide stimulated (p < 0.02) prostacyclin production by uterine arteries from both follicular- and luteal-phase sheep although phase of the estrous cycle did not affect prostacyclin responses (p = 0.56) to lipopolysaccharide. In contrast, uterine arteries from ovariectomized sheep treated with estradiol-17beta produced more prostacyclin (p < 0.001) in response to lipopolysaccharide than did uterine arteries from ovariectomized sheep treated with the vehicle control. There was no effect of phase (follicular or luteal) of the estrous cycle on either cyclooxygenase-1 or -2 gene expression. Lipopolysaccharide increased (p = 0.0002) gene expression of cyclooxygenase-2, but not cyclooxygenase-1, in both follicular- and luteal-phase ewes, which was significantly correlated (r2 = 0.91, p = 0.003) with uterine artery production of prostacyclin. Uterine arteries from follicular-phase sheep expressed significantly more nitric oxide synthase-III after lipopolysaccharide exposure than did uterine arteries from luteal-phase ewes (p = 0.03). In contrast, nitric oxide synthase-II was not detected in uterine arteries after lipopolysaccharide exposure. These results suggest that estrogen plays a role in regulating uterine artery responses to lipopolysaccharide.
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PMID:Estrogen and lipopolysaccharide stimulation of prostacyclin production and the levels of cyclooxygenase and nitric oxide synthase in ovine uterine arteries. 974 55

1. The effects of two chemically unrelated nitric oxide (NO)-releasing compounds were studied on prostacyclin production in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). The cells expressed cyclooxygenase-2 (COX-2) protein and produced prostacyclin by NS-398-sensitive manner suggesting that prostacyclin production derives principally by COX-2 pathway. 2. A novel NO-releasing oxatriazole derivative GEA 3175 (1-30 microm) inhibited LPS-induced production of prostacyclin in HUVECs in a dose-dependent manner being more potent than the earlier known NO-donor S-nitroso-N-acetylpenicillamine (SNAP). 3. The effects of the two NO-donors on prostacyclin synthesis were reversed when red blood cells were added into the culture indicating that the effects are due to NO released from the compounds. 4. Addition of exogenous arachidonic acid into the culture did not alter the inhibitory action of NO-donors suggesting that phospholipases are not the target of action of NO. 5. The NO-donors did not inhibit prostacyclin production in the presence of a selective COX-2 inhibitor NS-398. These data suggest that NO affects COX-2 pathway rather than has an overall effect on cyclooxygenases. 6. NO-releasing compounds did not alter the level of COX-2 protein expression in LPS-treated HUVECs as measured by Western blot analysis. 7. The results suggest that NO-donors inhibit the activity of COX-2 in human endothelial cells. A link between NO and the regulation of eicosanoid synthesis could represent an important mechanism in controlling vascular and inflammatory responses in pathophysiological states and during treatment with nitrovasodilators.
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PMID:Inhibition by nitric oxide-releasing compounds of prostacyclin production in human endothelial cells. 978 95

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.
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PMID:Pharmacological analysis of cyclooxygenase-1 in inflammation. 978 85

Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1beta with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2, 6-keto prostaglandin F1alpha, prostaglandin D2 and leukotriene B4 levels were determined by radioimmunoassay. Immunoblot analysis using isoform-specific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1beta treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1beta and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 microM concentration, and VSA inhibited lipopolysaccharide and interleukin 1beta stimulated prostaglandin E2, but not 6-keto prostaglandin F1alpha formation. SC-58125 inhibited lipopolysaccharide and interleukin-1beta stimulated 6-keto prostaglandin F1alpha but not prostaglandin E2 release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2 but not interleukin-1beta stimulated prostaglandin D2. While SC-58125 inhibited basal 6-keto prostaglandin-F1alpha formation it significantly increased basal prostaglandin E2 and prostaglandin D2 formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1beta induced 6-keto prostaglandin F1alpha production but not prostaglandin E2 production, it suggests that these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E2 production occurs through a cyclooxygenase-1 mediated mechanism. Prostaglandin D2 production appeared to be variably produced by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus.
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PMID:The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation. 983 94

Cyclooxygenase-2 (COX-2) is involved in the biosynthesis of prostanoids in the course of inflammatory reactions. This isoenzyme is regulated at the transcription level and many cells express COX-2 upon challenge with lipopolysaccharide (LPS) or pro-inflammatory cytokines. Since hepatocytes respond to LPS and pro-inflammatory stimuli, we investigated the expression of COX-2 in foetal and adult hepatocytes upon challenge with these substances. COX-2 was expressed in foetal hepatocytes incubated with LPS, tumour necrosis factor-alpha and interleukin-1beta. This response rapidly decreased after birth and was absent in hepatocytes from animals aged 2 days or more and treated under identical conditions. The expression of COX-2 was determined at the mRNA, protein and enzyme activity levels using Northern and Western blot, and following the synthesis of prostaglandin E2, respectively. The use of NS 398, a specific pharmacological inhibitor of COX-2, confirmed the expression of this isoenzyme in activated foetal hepatocytes. Synergism in COX-2 expression was observed between LPS, tumour necrosis factor-alpha and interleukin-1beta. Interleukin-6 and permeant analogues of cyclic AMP failed to induce COX-2 or to synergize with LPS. Also, transforming growth factor-beta inhibited the LPS- and pro-inflammatory cytokines-dependent expression of COX-2. These results indicate that foetal hepatocytes are competent to express COX-2 upon challenge with pro-inflammatory stimuli, a process lost completely in hepatocytes isolated from animals aged 2 days.
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PMID:Expression of cyclooxygenase-2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro-inflammatory cytokines. 986 62


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