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)

The prostacyclin analogue iloprost has been shown to inhibit effectively TNF-alpha production in human peripheral blood mononuclear leukocytes (PBMC) stimulated with bacterial lipopolysaccharide (LPS). The current paper set out to analyse further the possible mechanisms involved in the regulation of TNF-alpha synthesis by iloprost. Healthy human PBMC were challenged with Escherichia coli LPS and assessed for TNF-alpha gene transcription, mRNA stability and protein secretion. Iloprost reduced both steady-state TNF-alpha mRNA expression and protein release as assessed by Northern blot analysis, polymerase chain reaction and enzyme immunoassay. This effect was related both to a reduction of TNF-alpha transcriptional activity (as evaluated by nuclear run-on transcription analysis) and a decrease in TNF-alpha mRNA stability (as assessed by serial Northern blot analysis of TNF-alpha mRNA content in PBMC blocked with actinomycin D). When collectively assessed, these data demonstrate that iloprost regulates TNF-alpha synthesis at both transcriptional and post-transcriptional level.
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PMID:Inhibition of tumour necrosis factor production in endotoxin-stimulated human mononuclear leukocytes by the prostacyclin analogue iloprost: cellular mechanisms. 907 63

We evaluated the thrombin-stimulated production of prostacyclin (PGI2) by cultured human pulmonary artery smooth muscle cells (HPASMC) that were pretreated with cytokines (IL-1 beta, TNF alpha) and lipopolysaccharide (LPS). Cultured HPASMC, obtained from autopsied cases, were identified as smooth muscle cells by immune staining with mouse anti-human alpha-smooth muscle actin monoclonal IgG. A 3 hour incubation of HPASMC with LPS, IL-1 beta, or TNF alpha followed by a 10 min exposure to 2 U/ml thrombin was sufficient to generate a greater amount of PGI2 than observed in control cells. The increase in PGI2 production peaked after 8 h in the IL-1 beta- and TNF alpha-treated HPASMC, and continued to increase for 24 h in the LPS-treated HPASMC. We then investigated the effect of incubation time of thrombin on PGI2 production in HPASMC pretreated with cytokines or LPS for 24 h. PGI2 production by LPS- and cytokine-treated HPASMC peaked after a 15 min exposure to thrombin. In contrast, the exposure of LPS- or IL-1 beta-treated HPASMC to buffer seemed to increase the release of PGI2 for up to 30 min of incubation. However, the PGI2 released was less than that in the thrombin-stimulated HPASMC. After incubation with various concentrations of LPS or cytokines, the production of PGI2 by thrombin-stimulated HPASMC showed significant, dose-dependent increases beginning at 0.1 microgram/ml of LPS, 20 U/ml of IL-1 beta, and 50 U/ml of TNF alpha. We conclude that LPS, IL-1 beta, and TNF alpha enhanced both the basal and thrombin-stimulated production of PGI2 by HPASMC. This enhanced production of PGI2 might help in lowering the pulmonary vascular tone and modifying pulmonary hemodynamics in cytokine- or endotoxin-mediated inflammation and acute injury of the lung.
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PMID:Cytokines and lipopolysaccharide enhance basal and thrombin-stimulated production of PGI2 by cultured human pulmonary artery smooth muscle cells. 908 96

Both cell-matrix and cell-cell interactions are important regulators of the function of most human cells. In this study we investigated how these interactions controlled the production of vasodilators nitric oxide (NO), and prostacyclin (PGI2), in freshly isolated human umbilical vein endothelial cells (HUVECs). On the reconstituted extracellular matrix (ECM) Matrigel freshly isolated HUVECs treated with interleukin-1 beta, lipopolysaccharide, and interferon-gamma, produced more NO, but less PGI2, than on gelatin substratum. High cell density was essential for inducibility of NO production in cells plated on gelatin substratum, but not on ECM. In cells plated on gelatin substratum at low cell density, which mimicked conventional HUVEC culturing conditions, both inducible NO production and the inducible NO synthase (iNOS) mRNA levels, detected by competitive RT-PCR, were low. However, inducible PGI2 production remained high in these cells. Highest inducible NO productions were observed in HUVECs that presumably had best maintained their original differentiated phenotype. Thus our data imply that the inducible NO and PGI2 productions of freshly isolated HUVECs were differently controlled by the extracellular matrix and cell density. Our data suggest that both cell-matrix and cell-cell interactions may have a strong influence on the proinflammatory cytokine responses of human vascular endothelial cells.
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PMID:Inducible nitric oxide and prostacyclin productions are differently controlled by extracellular matrix and cell density in human vascular endothelial cells. 909 3

Endotoxin infusion (lipopolysaccharide from Escherichia coli 120 micrograms kg-1 i.v.) was titrated to produce hypercoagulability in rabbits and the effects of prostacyclin (PGI2) treatment (continuous infusion of 6 ng kg-1 min-1 i.v.) on coagulation variables, cardiorespiratory variables, and fibrin deposition in the microcirculation of vital organs were studied. PGI2 infusion did not influence the concentration of soluble fibrin, thrombelastographic variables, or systemic platelet aggregability. Fibrin deposition in the microcirculation of the liver and the lungs was reduced to 50% of that observed in untreated animals (p < 0.01). The antiplatelet properties of PGI2 were unable to reduce experimental endotoxin-induced systemic procoagulant turnover but improved organ perfusion during the initial phase of disseminated intravascular coagulation.
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PMID:Effects of prostacyclin substitution on systemic procoagulant turnover and cardiorespiratory variables in experimental hypercoagulability. 909 82

The enhanced nitric oxide (NO) and prostaglandin (PG) generation of activated macrophages is controlled by glucocorticoid-sensitive inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Negative feedback regulation of iNOS expression by the products of both pathways has been suggested, but their effects on COX-2 expression have not been examined. We hae investigated the effect of E- and l-series prostaglandins that activate adenylate cyclase (AC), forskolin (a direct activator of AC), and other agents that influence the cyclicAMP/cyclicGMP systems on the ability of E. coli endotoxin (lipopolysaccharide, LPS) to induce iNOS and COX-2 in the murine macrophage cell line J774. After a 2-hr pretreatment before adding endotoxin, PGE2, PGI2, forskolin, IBMX (isobutylmethylxanthine, a cyclicAMP/cyclicGMP phosphodiesterase inhibitor), 8-bromo cyclicAMP, and arachidonic acid itself all inhibited the expression of both iNOS and COX-2 (as shown by Western blotting) and reduced NO release and COX activity, whereas PGF2 alpha and 8-bromo cyclic GMP were only weakly effective. The effects of PGE2, PGI2, and forskolin were enhanced by cotreatment with IBMX. The suppression of LPS-induced iNOS induction by PGE2 was functionally significant, in that it protected against the mild cytotoxicity of the NO generated in response to endotoxin. These results provide the first direct evidence for the feedback regulatory suppression of COX-2 induction by a PG-driven cAMP-mediated process, and show that the modulation of iNOS and COX-2 induction shares common features. They also suggest that such modulation is normally held in check by high phosphodiesterase activity within these cells.
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PMID:Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages. 910

1. The role of nitric oxide (NO) in ischaemia-reperfusion injury to the heart continues to be debated. 2. The role of NO released during endotoxemia on myocardial reperfusion injury was examined in rats given saline or lipopolysaccharide (LPS, 10 mg. kg-1). 3. Aortic rings from LPS-treated rats showed a markedly decreased contractile response to both noradrenaline (NA) and U46619, and a diminished relaxation response to acetylcholine, thrombin and aggregating platelets. Treatment of rat aortic rings from LPS-treated rats with the NO synthesis inhibitor N omega-nitro-L-arginine (L-NOARG) reversed the diminished contractile response to NE and U46619. 4. Before ischaemia-reperfusion, baseline force of cardiac contraction (FCC) and coronary perfusion pressure (CPP) were lower and coronary flow was higher in hearts from LPS-treated rats (all P < 0.05 vs. saline-treated group). Treatment of hearts from LPS-treated rats with L-NOARG increased baseline FCC and CPP. 5. After ischaemia-reperfusion, hearts from saline-treated rats showed a 36 +/- 5% fall in FCC, a 38 +/- 6% rise in CPP and a 38 +/- 5% fall in coronary flow, whereas hearts from LPS-treated rats revealed only a 16 +/- 9% fall in FCC, a 10 +/- 3% rise in CPP and a 20 +/- 4% fall in coronary flow (all P < 0.05 vs. changes in saline-treated group). Fewer hearts from LPS-treated rats developed reperfusion arrhythmias (6% vs. 60% hearts from saline-treated rats, P < 0.02). Myocardial superoxide dismutase activity was higher in the LPS-treated group (P < 0.05). 6. NO synthesis, measured as formation of nitrite, was higher (P < 0.05) in cardiac and aortic tissues from LPS-treated rats. Prostacyclin (PGI2) release in coronary effluent was greater in LPS-treated rat hearts (P < 0.05 vs. saline-treated rats). 7. Thus LPS-treated hearts demonstrate a basal decrease in FCC and coronary vascular resistance. These hearts demonstrate a modest protection from reperfusion injury. Induction of NO synthesis, and possibly PGI2 release, may underlie cardioprotection from ischaemia-reperfusion.
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PMID:Reperfusion injury in the endotoxin-treated rat heart: reevaluation of the role of nitric oxide. 911 24

Cyclooxygenase-2, the inducible isoform of cyclooxygenase, is highly expressed in microglial cells activated by bacterial lipopolysaccharide and is a major regulatory factor in the synthesis of prostanoids, such as prostaglandins, prostacyclin and thromboxanes. Since prostanoids are potent modulators of inflammation, immune responses and neurotoxicity, the regulation of their synthesis may be crucial for balancing microglial neuroprotective and neurotoxic activities. The present study shows that expression of cyclooxygenase-2 and prostanoid production in cultured rat microglia activated by lipopolysaccharide is up-regulated by cyclic AMP (cAMP), as indicated by experiments performed in the presence of adenylyl cyclase activators, cAMP analogues and protein kinase A-specific inhibitors. Exogenous prostaglandin E2 (PGE2), which elevates the cAMP level in microglial cells, also increased the lipopolysaccharide-induced expression of cyclooxygenase-2 and production of thromboxane in a dose- and time-dependent manner. The observations that the lipopolysaccharide-induced prostanoid production was specifically increased by 11-deoxy-16,16-dm PGE2, a selective agonist at the PGE2 receptor EP2 coupled to the activation of adenylyl cyclase, and that the enhancing effect of PGE2 was partially prevented by specific inhibitors of adenylyl cyclase and protein kinase A, suggest that the up-regulation of cyclooxygenase-2 expression by PGE2 is mediated by cAMP, through a putative microglial EP2 receptor. Unexpectedly, non-steroidal anti-inflammatory drugs such as indomethacin and 6-methoxy naphthalene acetic acidic, which inhibit cyclooxygenase enzymatic activity and abrogate prostanoid synthesis, caused a moderate but consistent up-regulation of cyclooxygenase-2 expression. In conclusion, while the strong up-regulation of cyclooxygenase-2 expression by exogenous PGE2 appears to be mediated by EP2 receptors and cAMP, the limited down-regulation caused by anti-inflammatory drug treatments may be either due to arachidonic acid metabolites other than PGE2, or to PGE2 itself, acting through a distinct cAMP-independent signalling pathway.
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PMID:Up-regulation of cyclooxygenase-2 expression in cultured microglia by prostaglandin E2, cyclic AMP and non-steroidal anti-inflammatory drugs. 918 46

Acute lung injury is the end result of common pathways initiated by a variety of local or systemic insults leading to diffuse damage to the pulmonary parenchyma. Despite the accumulation of abundant information regarding the physiological and cellular basis of lung injury and increasingly sophisticated intensive care, an improvement in prognosis has lagged behind. It has become clear that there is not one mediator responsible for acute lung injury but rather a complex interplay exists between diverse proinflammatory (eg, lipopolysaccharide, complement products, cytokines, chemokines, reactive oxygen species, and eicosanoids) and anti-inflammatory (interleukin-10, interleukin-1-RA, PGI2) mediators. It is essential that we obtain a better understanding of the complexities of the acute inflammatory response if we are to successfully intervene to prevent or ameliorate tissue injury. The purpose of this review is to summarize recent developments that have contributed to our understanding of the basic mechanisms of lung injury. We focus on the persistence of the inflammatory response on a local and systemic level, including local mechanisms acting within the alveolar space regulating synthesis, release, and activation of inflammatory mediators; the balance of proteinases and antiproteinases; the abnormalities of surfactant; and the potential importance of endogenously released anti-inflammatory mediators. It is hoped that the results of these studies will provide insights into the pathogenesis of lung injury and lead to novel therapeutic strategies to prevent or ameliorate lung injury.
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PMID:Mechanisms of acute lung injury. 923 71

We have examined the bradykinin (BK)-stimulated production of prostacyclin (PGI2) by cultured human pulmonary artery smooth muscle cells (HPASMC) pretreated with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) or interferon gamma (IFN gamma). BK from 0.01 to 1 microM induced a dose-dependent increase in PGI2 production by HPASMC. A striking increase in PGI2 production in response to BK was observed in HPASMC which had been incubated with 1 microgram/ml LPS, 20 U/ml IL-1 beta, 50 U/ml TNF alpha or 100 U/ml IFN gamma. After incubation with various concentrations of LPS or cytokines, the production of PGI2 by BK-stimulated HPASMC showed significant, dose-dependent increases beginning at 0.1 microgram/ml of LPS, 2 U/ml of IL-1 beta and 5 U/ml of TNF alpha, while higher concentrations of IFN gamma failed to cause any further increase in PGI2 production. Our results indicate that BK is a potent agonist to stimulate HPASMC to produce PGI2. LPS, IL-1 beta and TNF alpha effectively enhanced BK-stimulated production of PGI2 by HPASMC, while IFN gamma had only a weak effect on BK-stimulated PGI2 production. Bradykinin-induced enhancement of PGI2 production by LPS, IL-1 beta and TNF alpha might be involved in the regulation of pulmonary vascular tension and prevent a paradoxical thrombogenic effect in endotoxin- or cytokine-mediated inflammation and acute lung injury. These experimental results suggest that vascular smooth muscle cells might actively control the vascular tension and blood supply by producing PGI2 in response to an agonist such as BK.
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PMID:Lipopolysaccharide and cytokines enhance bradykinin-stimulated production of PGI2 by cultured human pulmonary artery smooth muscle cells. 924 8

1. The prostanoid receptor(s) that mediates inhibition of bacterial lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) generation from human peripheral blood monocytes was classified by use of naturally occurring and synthetic prostanoid agonists and antagonists. 2. In human monocytes that were adherent to plastic, neither prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F(2 alpha) (PGF(2 alpha)) nor the stable prostacyclin and thromboxane mimetics, cicaprost and U-46619, respectively, promoted the elaboration of TNF alpha-like immunoreactivity, as assessed with a specific ELISA, indicating the absence of excitatory prostanoid receptors on these cells. 3. Exposure of human monocytes to LPS (3 ng ml-1, approximately EC84) resulted in a time-dependent elaboration to TNF alpha which was suppressed in cells pretreated with prostaglandin E1 (PGe1), PGE2 and cicaprost. This effect was concentration-dependent with mean pIC50 values of 7.14, 7.34 and 8.00 for PGE1, PGE2 and cicaprost, respectively. PGD2, PGF(2 alpha) and U-46619 failed to inhibit the generation of TNF alpha at concentrations up to 10 microM. 4. With respect to PGE2, the EP-receptor agonists, 16,16-dimethyl PGE2 (non-selective), misoprostol (EP2/EP3-selective), 11-deoxy PGE1 (EP2-selective) and butaprost (EP2-selective) were essentially full agonists as inhibitors of LPS-induced TNF alpha generation with mean pIC50 values of 6.21, 6.02, 5.67 and 5.59, respectively. In contrast to the results obtained with butaprost and 11-deoxy PGE1, another EP2-selective agonist, AH 13205, inhibited TNF alpha generation by only 21% at the highest concentration (10 microM) examined. EP-receptor agonists which have selectively for the EP1- (17-phenyl-omega-trinor PGE2) and EP3-receptor (MB 28,767, sulprostone) were inactive or only weakly active as inhibitors of TNF alpha generation. 5. Pretreatment of human monocytes with the TP/EP4-receptor antagonist, AH 23848B, at 10, 30 and 100 microM suppressed LPS-induced TNF alpha generation by 10%, 28% and 77%, respectively, but failed to shift significantly the location of the PGE2 concentration-response curves. 6. Given that AH 13205 was a poor inhibitor of TNF alpha generation, studies were performed to determine if it was a partial agonist and whether it could antagonize the inhibitory effect of PGE2. Pretreatment of human monocytes with 10 and 30 microM AH 13205 inhibited the generation of TNF alpha by 31% and 53%, respectively, but failed to shift significantly the location of the PGE2 concentration-response curves at either concentration examined. 7. Since PGD2 and 17-phenyl-omega-trinor PGE2 (EP1-agonist) did not suppress TNF alpha generation, the EP1/EP2/DP-receptor antagonist, AH 6809, was employed to assess if EP2-receptors mediated the inhibitory effect of PGE2. Pretreatment of human monocytes with 10 microM AH 6809 did not affect LPS-induced TNF alpha generation but produced a parallel 3.5 fold rightwards shift of the PGE2 concentration-response curve. 8. Collectively, these data suggest that human peripheral blood monocytes express at least two distinct populations of inhibitory prostanoid receptors that mediate inhibition of LPS-induced TNF alpha generation. One of these probably represents i.p. receptors based upon the selectivity of cicaprost for this subtype. The other population has the pharmacology of EP-receptors, but the rank of potency for a range of synthetic EP-receptor agonists was inconsistent with an interaction with any of the currently defined subtypes. Given the pharmacological behaviour of butaprost, AH 6809 and AH 23848B in these cells, we propose that multiple (EP2- and/or EP-4- and/or i.p.) or novel EP-receptors mediate the inhibitory effect of PGE2 on TNF alpha generation.
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PMID:Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-alpha generation. 929 41


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