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)

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.
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PMID:Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells. 1096 64

Studies investigating the effect of dietary fats on pro-inflammatory cytokine production by macrophages (M phis) have yielded conflicting results. We hypothesised that this may be due to the different capacities of the M phis studied commonly (resident, thioglycollate-elicited) to produce prostaglandin E(2)(PGE(2)) and leukotriene B(4)(LTB(4)) which inhibit and stimulate, respectively, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) production. To investigate this, male C57Bl6 mice were fed for 6 weeks on a low fat (LF) diet or on high fat diets which contained coconut oil (CO), olive oil (OO), safflower oil (SO) or fish oil (FO) as the main fat source. Production of TNF-alpha, IL-1 beta, PGE(2)and LTB(4)by lipopolysaccharide-stimulated resident and thioglycollate-elicited (i.e. inflammatory) peritoneal M phis was measured. PGE(2)production by both inflammatory and resident M phis was significantly decreased by FO feeding. FO also decreased LTB(4)production by resident M phis compared with LF feeding. Production of both cytokines by inflammatory M phis decreased with increasing unsaturation of the high fat diets, such that cells from FO-fed mice showed significantly decreased production of TNF-alpha and IL-1 beta compared to those from mice fed on each of the other diets. In contrast, resident M phis from mice fed FO showed increased TNF-alpha production compared to those from CO-fed mice. Thus, FO feeding decreases production of TNF-alpha and IL-1 beta by inflammatory M phis and increases production of TNF-alpha by resident M phis, at least in comparison to some other dietary fats. These results indicate the mechanisms by which dietary fats exert their effects upon pro-inflammatory cytokine production are most likely different for resident and inflammatory M phis.
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PMID:Activation state alters the effect of dietary fatty acids on pro-inflammatory mediator production by murine macrophages. 1097 97

In a previous work, we postulated that endothelial cells possess only the following 2 enzymes involved in prostanoid synthesis: cyclooxygenase and prostacyclin synthase. The present work focused on investigating the expression of prostaglandin (PG) E synthase (PGES) in vascular cells. After incubation of vascular smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) with [(14)C]arachidonic acid, the profile of prostanoid synthesis was assessed by HPLC. Untransformed PGH(2) released by the cells was evaluated as the difference in the formation of PGF(2alpha) in the incubations performed in the presence and in the absence of SnCl(2). Resting SMCs and SMCs stimulated with phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha formed PGE(2) and PGI(2) (evaluated as 6-oxo-PGF(1alpha)), and in the presence of SnCl(2) only a small amount of PGE(2) was deviated toward PGF(2alpha). In contrast, resting and stimulated HUVECs produced PGI(2), PGE(2), PGF(2alpha), and PGD(2), and SnCl(2) completely diverted PGE(2) and PGD(2) toward PGF(2alpha). Reverse transcriptase-polymerase chain reaction analysis shows that mRNA encoding for PGES was not present in HUVECs and in endothelial cells from saphenous vein. Nevertheless, PGES was expressed in SMCs and induced by IL-1beta and TNF-alpha, and by PMA and LPS, although to a lesser extent. Whereas SMC stimulation led to an increase in the synthesis of PGE(2) and PGI(2) but not of untransformed PGH(2), stimulation of endothelial cells resulted in an enhanced release of the vasoconstricting prostanoid PGH(2).
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PMID:Human vascular smooth muscle cells but not endothelial cells express prostaglandin E synthase. 1098 43

Exposure of rat glial cells to lipopolysaccharide (LPS) induces the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), the inflammatory mediators implicated in the pathogenesis of seizures and epilepsy. To determine the effect of the anticonvulsant drug carbamazepine (CBZ) on the inflammatory process, LPS-stimulated rat primary glial cultures were exposed to this agent. Dose-dependent inhibition of NO and PGE(2) production was observed of up to 77 and 88%, respectively. Furthermore, a prominent (94%) decline in the secretory isoform of phospholipase A(2) (sPLA(2)) activity was found in response to CBZ and could contribute to the inhibition of PGE(2) production. Cumulatively, our findings point to the anti-inflammatory effect of CBZ on non-neuronal cells, which might, in part, contribute to its anticonvulsive effect.
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PMID:Inhibitory effect of carbamazepine on inflammatory mediators produced by stimulated glial cells. 1100 Apr 48

Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol (gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively. The major metabolite of dietary gammaT, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), also exhibited an inhibitory effect, with an IC(50) of approximately 30 microM in these cells. In contrast, alpha-tocopherol at 50 microM slightly reduced (25%) PGE(2) formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. gamma-CEHC also inhibited PGE(2) synthesis when exposed for 1 h to COX-2-preinduced cells followed by the addition of arachidonic acid (AA), whereas under similar conditions, gammaT required an 8- to 24-h incubation period to cause the inhibition. The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease prevention.
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PMID:gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. 1100 41

The action of prostaglandin E(2) (PGE(2)) in the preoptic area is thought to play an important role in producing fever. Pharmacologic evidence suggests that, among the four subtypes of E-series prostaglandin (EP) receptors, i.e., EP(1), EP(2), EP(3), and EP(4), the EP(1) receptor mediates fever responses. In contrast, evidence from mice with EP receptor gene deletions indicates that the EP(3) receptor is required for the initial (<1 hour) fever after intravenous (i.v.) lipopolysaccharide (LPS). To investigate which subtypes of EP receptors mediate systemic infection-induced fever, we assessed the coexpression of Fos-like immunoreactivity (Fos-IR) and EP(1-4) receptor mRNA in nuclei in the rat hypothalamus that have been shown to be involved in fever responses. Two hours after the administration of i.v. LPS (5 microg/kg), Fos-IR was observed in the ventromedial preoptic nucleus, the median preoptic nucleus, and the paraventricular hypothalamic nucleus. In these nuclei, EP(4) receptor mRNA was strongly expressed and the Fos-IR intensely colocalized with EP(4) receptor mRNA. Strong EP(3) receptor mRNA expression was only seen within the median preoptic nucleus but Fos-IR showed little coexpression with EP(3) receptor mRNA. EP(2) receptor mRNA was not seen in the PGE(2) sensitive parts of the preoptic area. Although approximately half of the Fos-immunoreactive neurons also expressed EP(1) receptor mRNA, EP(1) mRNA expression was weak and its distribution was so diffuse in the preoptic area that it did not represent a specific relationship. In the paraventricular nucleus, EP(4) mRNA was found in most Fos-immunoreactive neurons and levels of EP(4) receptor expression increased after i.v. LPS. Our findings indicate that neurons expressing EP(4) receptor are activated during LPS-induced fever and suggest the involvement of EP(4) receptors in the production of fever.
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PMID:Relationship of EP(1-4) prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses. 1105 22

The expression and function of prostaglandin (PG) E(2) receptors were examined in mouse neutrophils exudated into the peritoneal cavity by casein treatment. Expressions of the EP2 and EP4 receptors were detected in neutrophils by Northern blot, but those of EP1 and EP3 receptors were not detected by RT-PCR. EP2-selective agonist, ONO-AE1-259, and EP4-selective agonist, ONO-AE1-329, stimulated cAMP formation in the cells. PGE(2) affected the TNF-alpha and IL-6 production in lipopolysaccharide (LPS)-treated neutrophils; it suppressed the TNF-alpha production and enhanced the IL-6 production. The PGE(2) effects were mimicked by dibutyryl cAMP. This is the first study of the enhancement of IL-6 production by cAMP-elevating reagents in neutrophils. Using neutrophils from EP2- and EP4-deficient mice in combination with EP2- and EP4-selective agonists, it was found that the augmentation of IL-6 was mediated mainly by the EP2 receptor and the suppression of TNF-alpha by the EP4 receptor and partially by the EP2 receptor. These findings indicate that casein-induced peritoneal neutrophils express Gs-coupled PGE(2) receptors, EP2 and EP4, which might differentially regulate the LPS-induced production of TNF-alpha and IL-6.
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PMID:Prostaglandin E(2) receptors, EP2 and EP4, differentially modulate TNF-alpha and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils. 1107 76

Prostaglandins (PG), which are responsible for a large array of biological functions in eukaryotic cells, are produced from arachidonic acid by phospholipases and cyclooxygenase enzymes COX-1 and COX-2. We demonstrated that PG levels in cells were partly controlled by a regulatory protein, phospholipase A2 (PLA2)-activating protein (PLAA). Treatment of murine macrophages with lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha increased PLAA levels at early time points (2-30 min), which correlated with an up-regulation in cytosolic PLA2 and PGE2 levels. Both COX-2 and secretory PLA2 were also increased in lipopolysaccharide-stimulated macrophages, however, at later time points of 4-24 h. The role of PLAA in eicosanoid formation in macrophages was confirmed by the use of an antisense plaa oligonucleotide. Within amino acid residues 503-538, PLAA exhibited homology with melittin, and increased PGE(2) production was noted in macrophages stimulated with melittin. In addition to PLA2, we demonstrated that activation of phospholipase C and D significantly controlled PGE2 production. Finally, increased antigen levels of PLAA, COX-2, and phospholipases were demonstrated in biopsy specimens from patients with varying amounts of intestinal mucosal inflammation, which corresponded to increased levels of phospholipase activity. These results could provide a basis for the development of new therapeutic tools to control inflammation.
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PMID:Prostaglandin levels in stimulated macrophages are controlled by phospholipase A2-activating protein and by activation of phospholipase C and D. 1109 54

Using human blood monocytes (for determination of cyclooxygenase-2 (COX-2) mRNA by RT-PCR) and human whole blood (for prostanoid determination), the present study investigates the influence of the second messenger cAMP on lipopolysaccharide (LPS)-induced COX-2 expression with particular emphasis on the role of prostaglandin E(2) (PGE(2)) in this process. Elevation of intracellular cAMP with a cell-permeable cAMP analogue (dibutyryl cAMP), an adenylyl cyclase activator (cholera toxin), or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) substantially enhanced LPS-induced PGE(2) formation and COX-2 mRNA expression, but did not modify COX-2 enzyme activity. Moreover, up-regulation of LPS-induced COX-2 expression was caused by PGE(2), butaprost (selective agonist of the adenylyl cyclase-coupled EP(2) receptor) and 11-deoxy PGE(1) (EP(2)/EP(4) agonist), whereas sulprostone (EP(3)/EP(1) agonist) left COX-2 expression unaltered. Abrogation of LPS-induced PGE(2) synthesis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mRNA levels that was restored by exogenous PGE(2) and mimicked by S(+)-flurbiprofen and ketoprofen. Overall, these results indicate a modulatory role of cAMP in the regulation of COX-2 expression. PGE(2), a cAMP-elevating final product of the COX-2 pathway, may autoregulate COX-2 expression in human monocytes via a positive feedback mechanism.
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PMID:Cyclooxygenase-2 expression in lipopolysaccharide-stimulated human monocytes is modulated by cyclic AMP, prostaglandin E(2), and nonsteroidal anti-inflammatory drugs. 1109 85

We previously reported that intracolonic administration of enprostil, a prostaglandin-E(2) (PGE(2)) analogue, had therapeutic effects on acute colitis induced in rodents by dextran sulfate sodium (DSS). In addition, production of growth-regulated gene product/cytokine-induced neutrophil chemoattractant-1 [GRO/CINC-1; an interleukin(IL)-8 like cytokine] was suppressed in the inflamed tissues. In the present study we used a human colon cancer cell line (HT-29) to investigate enprostil effects on the IL-8 production of intestinal epithelial cells stimulated by various stimulants. In a MTT assay, concentrations of enprostil >10(-5)M had cytotoxitic effects on HT-29 cells. Furthermore, 10(-6) M enprostil suppressed IL-8 production in HT-29 cells, SW620 and CaCo2 stimulated with interleukin-1 beta (IL-1 beta) or lipopolysaccharide (LPS), but did not suppress this response when cells were stimulated with tumour necrosis factor (TNF)-alpha. These results suggest that enprostil affects a point in the pathway between the IL-1 receptor or LPS receptor and nuclear factor-kappa B(NF-kappa B), without affecting the pathway between the TNF receptor and NF-kappa B, with the latter factor being required for the IL-8 gene transcription. The therapeutic effect of exogenous enprostil on DSS colitis may involve the inhibition of IL-8 production in colonic epithelial cells stimulated by IL-1 beta or LPS.
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PMID:Enprostil, a prostaglandin-E(2) analogue, inhibits interleukin-8 production of human colonic epithelial cell lines. 1111 62


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