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)

Prostaglandins (PGs) released by cultured rat Kupffer cells in response to stimulation with lipopolysaccharide (LPS) or ethanol were extracted from culture media, separated by HPLC and measured by radioimmunoassay. LPS (0.5-5 micrograms/ml) enhanced, after a 3-4 hrs lag period, the production of PGE2 (7-10 fold by 24 hrs), thromboxane B2 (2-3 fold) and PGD2. PG 6-keto-F1 alpha, PGF2 alpha (20-50% each). This effect was not inhibited by 30 microM aspirin but was reduced by dexamethasone. Ethanol (25-85 mM) gradually increased the release of PGE2 (40-90% by 24 hrs) and other PGs (10-30%), with 30 microM aspirin eliminating this effect. When added together with LPS, ethanol potentiated the endotoxin action. We suggest that LPS causes synthesis of the inducible cyclooxygenase-2 form in Kupffer cells, whereas ethanol exerts its effect via the pre-existing cyclooxygenase-1 mainly by increasing the free arachidonic acid content.
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PMID:Secretion of prostaglandins elicited by lipopolysaccharide and ethanol in cultured rat Kupffer cells. 748 10

The discovery of a second cyclooxygenase has provided fresh impetus to the search for new anti-inflammatory drugs. The second enzyme is effectively absent from healthy tissues but its levels rise dramatically during inflammation. It can be induced in migratory cells by bacterial lipopolysaccharide, cytokines and growth factors. The constitutive cyclooxygenase-1 (COX-1) can thus be considered a "housekeeping" enzyme, in contrast to cyclooxygenase-2 (COX-2) which is activated by tissue damage. Both enzymes have a molecular weight of around 70 kDa and similar Km and Vmax values for their reaction with arachidonic acid. Several non steroid anti-inflammatory drugs which have more than 1,000 fold selectivity for COX-2 over COX-1 are in the early stages of drug development.
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PMID:New insights into the mode of action of anti-inflammatory drugs. 766 22

Studies were conducted to characterize a human monocyte model where the role of the 85-kDa phospholipase A2 (PLA2) in prostanoid formation could be evaluated. The presence of an immunologically related 85-kDa PLA2 and type II 14-kDa PLA2 was demonstrated in human monocytes and their roles examined in lipopolysaccharide (LPS)-induced monocyte prostaglandin E2 (PGE2) formation. Exposure of human monocytes to LPS over 18 h resulted in the up-regulation of the mitogen-inducible cyclooxygenase-2 and was accompanied by production and release of prostaglandin E2 but not leukotriene C4. This coincided with a 2-fold increase in the 85-kDa PLA2 protein and activity levels. In contrast, there was no effect on the type II 14-kDa-like PLA2 activity measured in the 100,000 x g particulate fraction nor did LPS induce the release of type II 14-kDa PLA2 into the medium. Treatment with cycloheximide over 18 h resulted in a time-dependent decrease in cytosolic 85-kDa PLA2 protein and activity (half-life = 4 h), but there was no change in the particulate type II 14-kDa-like PLA2 activity. Monocytes were therefore exposed to an 85-kDa PLA2 initiation site-directed antisense oligonucleotide which specifically decreased the cytosolic 85-kDa PLA2 protein levels and activity in a concentration-dependent manner. This had no effect on the cyclooxygenase-2 (protein mass or the ability to convert arachidonic acid to PGE2) or the particulate fraction sn-2 acylhydrolytic activity but was associated with a decrease in LPS-induced PGE2 production. Taken together, these data support a role for the cytosolic 85-kDa PLA2 in LPS-induced monocyte PGE2 formation.
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PMID:Suppression of monocyte 85-kDa phospholipase A2 by antisense and effects on endotoxin-induced prostaglandin biosynthesis. 792 10

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

To examine the possible role of increased vascular permeability in the circulatory shock induced by endotoxin (lipopolysaccharide), we examined whether lipopolysaccharide elicits plasma extravasation in the skin of ddY strain mice. We also studied whether nitric oxide (NO) and prostaglandins may mediate the lipopolysaccharide-induced increase in vascular permeability. Subcutaneous injection of lipopolysaccharide (100-400 micrograms/site) induced a dose-related and delayed increase in vascular permeability at the injection site as determined by the leakage of pontamine sky blue. Concurrent administration of aminoguanidine (a putative inducible NO synthase inhibitor) (10 mg/kg, i.v.) inhibited the lipopolysaccharide (400 micrograms/site)-induced dye leakage by 71%. N(G)-Nitro-L-arginine methyl ester (an inhibitor for both constitutive and inducible NO synthase) (10 and 20 mg/kg, i.v.) inhibited the lipopolysaccharide-induced dye leakage by 36% and 54%, respectively, whereas the inactive enantiomer, N(G)-nitro-D-arginine methyl ester (10 mg/kg, i.v.), had no effect. Pretreatment with an intraperitoneal injection of dexamethasone (500 micrograms/kg) or indomethacin (a cyclooxygenase-1 and -2 inhibitor) (5 mg/kg) almost completely inhibited the response induced by lipopolysaccharide, by 96% and 84%, respectively. [N-(2-Cyclohexyloxy-4-nitrophenyl) methanesulphonamide (a cyclooxygenase-2-specific inhibitor) (0.01-1 mg/kg, i.p.) also induced a dose-related inhibition of dye leakage elicited by lipopolysaccharide: 38% and 80% suppression at the doses of 0.1 and 1 mg/kg, respectively. Cycloheximide (a protein biosynthesis inhibitor) (35 mg/kg, s.c.) suppressed the effect of lipopolysaccharide by 74%. These results suggest that the increase in vascular permeability induced by lipopolysaccharide is mediated by both NO and prostaglandins and that synthesis of inducible NO synthase and cyclooxygenase-2 may be involved in this effect of lipopolysaccharide.
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PMID:Role of nitric oxide and prostaglandins in lipopolysaccharide-induced increase in vascular permeability in mouse skin. 866 58

An inducible form of cyclooxygenase-2 (COX-2) has been shown to be upregulated in vitro by various pro-inflammatory agents, such as lipopolysaccharide, IL-1 and TNF, COX-2 appears to be responsible for the increase in prostaglandin synthesis at the site of inflammation. To examine the involvement of COX-2 in inflammation, we analysed the expression of this gene in human rheumatoid arthritis (RA) and in rat adjuvant-induced arthritis. Immunocytochemical studies of synovial membrane biopsies from human RA, osteoarthritic (OA) and normal joints using a COX-2 specific antibody showed positive staining in RA, but not in normal synovial membranes. Specifically, expression of COX-2 was detected in synovial lining cells, lymphoid aggregates and endothelial cells of blood vessels. Although some positive staining was observed in the OA joints, the number of stained cells was dramatically lower and the staining of the cells was less intense than in the rheumatoid tissue. By reverse transcription and polymerase chain reaction analysis, COX-2 mRNA was detected in the rat adjuvant arthritic limb, whereas no COX-2 mRNA was detectable in the normal limb. These observations indicate that COX-2 expression is upregulated in inflammatory joint disease and that COX-2 is a potential therapeutic target for specific inhibition.
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PMID:Expression of cyclooxygenase-2 in human and an animal model of rheumatoid arthritis. 876 Nov 81

Hypoosmotic exposure (205 mosmol/l) of rat liver macrophages together with lipopolysaccharide (LPS) inhibited the LPS-induced tumor necrosis factor-alpha (TNF-alpha) release by about 60% and markedly diminished the LPS-induced increase of TNF-alpha mRNA levels. Hyperosmotic exposure (405 mosmol/l) had no effect on total TNF-alpha release, however, both TNF-alpha accumulation in the medium and the LPS-induced increase of TNF-alpha mRNA levels were significantly delayed under these conditions. This delay was abolished upon addition of betaine, which acts as an osmolyte in Kupffer cells. When LPS was added to Kupffer cells that had been preexposed to hyperosmotic medium for 24 h, the LPS-induced TNF-alpha release was inhibited by 90% when compared to normoosmotic conditions. Likewise, the LPS-induced increase in TNF-alpha mRNA levels was largely abolished. Inhibition of TNF-alpha release and of the increase in the TNF-alpha mRNA level in response to hyperosmolarity/LPS, however, was largely overcome when indomethacin or betaine was present during the hyperosmotic preincubation period. Because betaine has recently been shown to inhibit the hyperosmolarity-induced induction of cyclooxygenase-2 and stimulation of prostaglandin production, these findings suggest that the effect of betaine in restoring the LPS-induced TNF-alpha response in hyperosmotically exposed Kupffer cells is mediated by an inhibition of prostaglandin synthesis. The findings point to a regulatory role of cell volume and betaine for TNF-alpha production by liver macrophages, suggesting a new role of osmolytes in modulating immune function.
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PMID:Modulation of tumor necrosis factor-alpha release by anisoosmolarity and betaine in rat liver macrophages (Kupffer cells). 876 92

We have used purified microglial cultures obtained from neonatal rat brains to study some aspects of the regulation of prostanoid production in these cells. We found that nitric oxide, which is released into the culture medium along with prostanoids when the cells are exposed to lipo-polysaccharide (1-100 ng/ml), can down-regulate prostanoid biosynthesis. Indeed, the abrogation of endogenous nitric oxide production, obtained by depleting the medium of the precursor L-arginine or by blocking the activity of nitric oxide synthase by the specific inhibitor NG-monomethyl-L-arginine, led to a remarkable increase in lipopolysaccharide-induced prostanoid release. Moreover, the nitric oxide-generating compound 3-morpholinosydnonimine caused a substantial reduction of prostanoid formation, in the absence of endogenous nitric oxide, suggesting that both endogenous and exogenous nitric oxide may inhibit the induced prostanoid production. We also found that interferon-gamma potentiated the effect of lipopolysaccharide on nitrite accumulation as previously described by others and depressed the lipopolysaccharide-evoked production of prostaglandin E2, prostaglandin D2, and thromboxane. It is interesting that the inhibitory effect of interferon-gamma on prostanoid production did not appear to depend on the potentiation of NO release, as it was present also when the endogenous synthesis of nitric oxide was abrogated. Additional experiments showed that interferon-gamma and nitric oxide act mainly by down-regulating the lipopolysaccharide-induced enzymatic activity and expression (analyzed by western blot) of cyclooxygenase-2. Our data indicate that microglial prostanoid biosynthesis induced by proinflammatory stimuli, such as lipopolysaccharide, is tightly regulated by nitric oxide. Interferon-gamma appears to affect the balance between these local mediators by favoring nitric oxide production and inhibiting the prostanoid cascade and may thus contribute to the modulation of inflammation, local immune reactivity, and neuronal damage.
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PMID:Interferon-gamma and nitric oxide down-regulate lipopolysaccharide-induced prostanoid production in cultured rat microglial cells by inhibiting cyclooxygenase-2 expression. 878 24

We previously showed that intraperitoneal injection of lipopolysaccharide induced cyclooxygenase-2 (COX-2) mRNA in as yet unidentified cells of blood vessels and leptomeninges in the rat brain and proposed a possible role of these cells as the source of prostaglandin E2 in the genesis of fever (Cao et al., Brain Res., 697 (1995) 187-196). In the present study, to proceed further with this line of research, we addressed the following two questions: first, does a pyrogenic dose of interleukin-1 beta (IL-1 beta), an endogenous pyrogen, induce COX-2 mRNA in the brain blood vessels and leptomeninges? Secondly, if it does, what type of cells are positive for COX-2 mRNA? Intraperitoneal injection of recombinant human IL-1 beta (30 micrograms/kg) induced fever in rats and an in situ hybridization study revealed that faint but significant COX-2 mRNA signals appeared in the blood vessels and leptomeninges at 1.5 h after the injection (the early rising phase of fever). The mRNA signals increased in number and intensity at 4 h (early plateau phase), decreased at 6.5 h (early recovery phase), and completely disappeared by 10 h after the injection (late recovery phase). The COX-2 mRNA positive cells in the blood vessels were likely to be the endothelial cells since the corresponding cells in the adjacent mirror-imaged section also expressed mRNAs for intracellular adhesion molecule-1 and the type-I interleukin-1 receptor, although those in the leptomeninges still remained unidentified. These results imply that circulating IL-1 beta acts on its receptor on the endothelial cells of the brain vasculature to induce COX-2 mRNA, which is possibly responsible for the elevated level of PGE2 seen during fever.
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PMID:Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. 889 9

To clarify the role of vitamin E (alpha-tocopherol) for the induction of cyclooxygenase-2 (COX-2) in rat macrophages stimulated by lipopolysaccharide (LPS), vitamin E-enriched macrophages were prepared by intraperitoneal injection of vitamin E for 6 days at a rate of 5 mg per day. The production of PGE2 was increased in dose- and time-dependent manners by addition of LPS in both control and vitamin E-enriched peritoneal macrophages. The maximum effect of LPS was observed in 12 h at concentration of 5 micrograms/ml. By analyzing COX-2 mRNA level by Northern blot and COX-2 enzyme mass and phosphotyrosine by Western blot, it was revealed that the increase of PGE2 production reflected the induction of COX-2 expression through activation of tyrosine kinase. Vitamin E failed to inhibit PGE2 production in LPS-stimulated macrophages; however, genistein, a tyrosine kinase inhibitor, completely inhibited the production at 100 microM. These results suggest that vitamin E does not inhibit COX-2 expression via LPS-mediated tyrosine kinase signal transduction pathway.
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PMID:Effect of vitamin E on expression of cyclooxygenase-2 in lipopolysaccharide-stimulated rat macrophages. 895 37


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