Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined in the human T-cell line Jurkat the interaction between the activation through the T-cell receptor/CD3 complex and the adenylate cyclase pathway. OKT3, an anti-CD3 monoclonal antibody, did not activate by itself adenylate cyclase but produced a 3-7-fold increase of the cAMP accumulation induced by indirect (chloroadenosine, PGE2) or direct (forskolin) agonists of adenylate cyclase. A more detailed study with forskolin showed that OKT3 enhanced the effect of low concentrations of the agonist without affecting the maximal capacity of cAMP synthesis of the cells. The same concentrations of OKT3 produced both the enhancement of the adenylate cyclase pathway and the activation of phospholipase C. The enhancement by OKT3 of the adenylate cyclase pathway was inhibited by 0.5 microM staurosporine, a potent inhibitor of protein kinases, including tyrosine kinases and protein kinase C, whereas it was not inhibited by H7, a specific inhibitor of PKC. Staurosporine, at the same concentration, also inhibited the OKT3-induced activation of phospholipase C, a tyrosine kinase-dependent process. Taken together, these data indicate that activation of T-cell through the T-cell receptor enhances the adenylate cyclase pathway by a tyrosine protein kinase-dependent mechanism.
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PMID:T-cell antigen receptor-mediated enhancement of the adenylate cyclase pathway depends on tyrosine protein kinases. 838 29

We have evaluated the specific activity of phospholipase A2 (PLA2) and phosphatidylinositol-specific phospholipase C (PLC) in human amnion cells in monolayer culture that had not (CTL) or that had been treated with vanadate (VAN) and/or mouse epidermal growth factor (mEGF) for 4 h. It is known that both agents stimulate prostaglandin (PG) E2 synthesis in these cells. Phospholipase enzyme activities were determined in the 750 x g supernatant fraction of amnion cell homogenates under optimal in vitro conditions. The specific activity of PLA2 ranged from 1.1 to 1.25 nmol/mg protein/0.5 h and that of phosphatidylinositol-specific PLC from 1.04 to 1.2 mumol/mg protein/h. Treatment of amnion cell cultures with VAN and/or mEGF had no statistically significant effect on the specific activities of either phospholipases. Thus, we conclude that the stimulation of PGE2 production by VAN and mEGF is not due to an increase in the release of arachidonic acid from glycerophospholipid storage forms in human amnion cells.
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PMID:The effects of vanadate and epidermal growth factor on the specific activities of phospholipase A2 and phosphatidylinositol-specific phospholipase C in human amnion cells. 840 23

Tumor necrosis factor-alpha (TNF-alpha), a known pro-inflammatory cytokine, has been suggested to play a role in the pathogenesis of inflammatory bowel disease (IBD) by mediating damage to the intestinal epithelial cells. The present study demonstrates that TNF-alpha potentiates release and metabolism of 14C-labeled arachidonic acid (14C-AA) in cultured intestinal epithelial cells (INT 407). Although TNF-alpha on its own was but a weak stimulator of cellular 14C-AA turnover, it significantly potentiated the release of 14C-AA and 14C-labeled prostaglandin E2(14C-PGE2) after stimulation with three known phospholipase A2 activators: phospholipase. C from Clostridium perfringens, the calcium ionophore A23187, and the phorbol ester 4-beta-phorbol-12-myristate-13-acetate (PMA). The phospholipase A2 inhibitor quinacrine significantly reduced both AA and PGE2 release after combined stimulation with phospholipase C and TNF-alpha. In contrast to its effect on the AA turnover, TNF-alpha did not affect the phospholipase C-stimulated production of platelet-activating factor (PAF-acether). Taken together, these findings indicate that a) TNF-alpha potentiates phospholipase A2-stimulated AA release from cultured intestinal epithelial cells; b) TNF-alpha may stimulate phospholipase A2-dependent AA release without affecting the formation of PAF-acether and c) pretreatment with TNF-alpha potentiates the formation of PGE2 after stimulation with phospholipase A2 activators. In summary, the present investigation points to the possibility that TNF-alpha may stimulate intestinal epithelial cells to produce biologically active AA metabolites and that this stimulation may be modulated by components of the intestinal luminal content, like bacterial toxins.
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PMID:Tumor necrosis factor-alpha potentiates phospholipase A2-stimulated release and metabolism of arachidonic acid in cultured intestinal epithelial cells (INT 407). 848 66

The adequate biological function of the renin-angiotensin system in blood pressure regulation and volume control involves additional factors for a fully balanced response. This includes arachidonic acid-derived lipid mediators, the eicosanoids. Angiotensin II (Ang II) causes (AT1)-receptor mediated stimulation of phospholipase C, resulting in generation of IP3 (inositol triphosphate) and activation of protein kinase C, elevated cytosolic Ca+ and stimulation phospholipase A2. These processes culminate in the generation of cell-specific eicosanoids and their autocrine action on the generating cell or paracrine effects on cells in the vicinity. In vascular tissue, liberated arachidonic acid is mainly converted into vasodilator prostaglandins, i.e. prostacyclin (PGI2) and PGE2. These prostaglandins may attenuate any direct Ang II-induced vasoconstriction, lower systemic vascular resistance and stimulate renal sodium excretion. In some vessels, arachidonic acid released by Ang II may also be converted to vasoconstrictor eicosanoids, i.e. thromboxane A2, PGF2 alpha and 12-HETE. The biological significance of endogenous eicosanoid generation becomes evident if vasoactive eicosanoids become limiting factors for maintaining homoiostasis, i.e. in the fetal circulation, Bartter's syndrome and congestive heart failure where vasodilating eicosanoids (PGE2, PGI2) are involved in maintenance of low vascular resistance and reduced or absent vasoconstriction by Ang II. Vasoconstrictor eicosanoids (thromboxane A2, PGF2 alpha, 12-HETE) contribute to high blood pressure in (renovascular) hypertension and pregnancy-induced hypertension. Alternatively, generation of vasodilator prostaglandins may be reduced in these situations. The vascular renin-angiotensin system is subject to the action of a number of drugs and chemicals, most notably specific inhibitors of the angiotensin-converging enzyme and drugs affecting kidney function (furosemide) and/or vessel tone (propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin-mediated actions of the renin-angiotensin system. 849 70

Phosphoinositide breakdown is thought to be important in regulating a variety of transmembrane signal transduction in the action of oxytocic agent during uterine smooth muscle contraction. We investigated the effects of oxytocin and prostaglandins (PGE2 and PGF2 alpha) on phosphoinositide hydrolysis in the myometrium taken from non-pregnant and pregnant rabbits by measuring the accumulation of total inositol phosphates (IP). Oxytocin strongly, and PGE2 and PGF2 alpha slightly but significantly, stimulated IP production in both the non-pregnant and pregnant myometria. Oxytocin more markedly accelerated the IP production in pregnant myometrium than in non-pregnant myometrium. However, IP production stimulated by PGE2 and PGF2 alpha was much the same in non-pregnant and pregnant myometria. The amount and time course of the increase in the production of the total IPs by oxytocin are quite different from those by PGs. It seems that the mechanism by which oxytocin stimulates phospholipase C is different from that of the PGs. It is suggested that transmembrane signalling pathways of phosphoinositide hydrolysis play an important role in the each mechanism.
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PMID:Oxytocin, PGE2 and PGF2 alpha stimulate the production of inositol phosphates in the rabbit myometrium. 850 3

PGE2 is a powerful modulator of uterine contractility, but there is uncertainty as to which receptor subtypes (EP1, EP2, EP3, or EP4), G proteins, and second messenger systems are activated by PGE2 in myometrium. Here we show that in cultured human myometrial cells, PGE2 (1-100 microM) activates phospholipase C (PLC) up to 500% over the control level and elevates intracellular calcium ([Ca2+]i) from the resting level of 60-90 nM up to 350 nM in a concentration-dependent manner. Stimulation by the receptor subtype-selective analogs GR63799X (EP3), sulprostone (EP3 > EP1), and misoprostol (EP3 > EP2 > EP1) indicates that these effects are transmitted through EP3 receptors. Both effects are resistant to pertussis toxin (PT). Lower concentrations of PGE2 (1-300 nM) increase [Ca2+]i via a PT-sensitive pathway, without PLC activation. This [Ca2+]i increase occurs after an inverse dose-related delay and is inhibited by the selective EP1 antagonist AH6809 and calcium channel blockers. By comparison, oxytocin stimulates PLC up to 1000% over the control level and elevates [Ca2+]i up to 800 nM in a concentration-dependent manner without any measurable delay; both effects are partly sensitive to PT. These data provide functional evidence for the presence of different stimulatory mechanisms for PGE2 in myometrium: 1) a low affinity receptor (probably EP3D) that activates PLC through a PT-insensitive pathway; and 2) a high affinity receptor (probably EP1), independent from PLC and involving a PT-sensitive G protein (G(i)?). Both pathways lead to elevation of [Ca2+]i.
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PMID:Prostaglandin E2 activates phospholipase C and elevates intracellular calcium in cultured myometrial cells: involvement of EP1 and EP3 receptor subtypes. 864 Dec 11

Lipid bodies, lipid rich cytoplasmic inclusions, are characteristically abundant in vivo in leukocytes associated with inflammation. Because lipid bodies are potential reservoirs of esterified arachidonate and sites at which eicosanoid-forming enzymes may localize, we evaluated mechanisms of lipid body formation in neutrophils (PMN). Among receptor-mediated agonists, platelet activating factor (PAF), but not C5a, formyl-methyl-phenylalanine, interleukin 8, or leukotriene (LT) B4, induced the rapid formation of lipid bodies in PMN. This action of PAF was receptor mediated, as it was dose dependently inhibited by the PAF receptor antagonist WEB 2086 and blocked by pertussis toxin. Lipid body induction by PAF required 5-lipoxygenase (LO) activity and was inhibited by the 5-lipoxygenase-activating protein antagonist MK 886 and the 5-LO inhibitor zileuton, but not by cyclooxygenase inhibitors. Corroborating the dependency of PAF-induced lipid body formation on 5-LO, PMN and macrophages from wild-type mice, but not from 5-LO genetically deficient mice, formed lipid bodies on exposure to PAF both in vitro and in vivo within the pleural cavity. The 5-LO product inducing lipid body formation was not LTB4 but was 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE], which was active at 10-fold lower concentrations than PAF and was also inhibited by pertussis toxin but not by zileuton or WEB 2086. Furthermore, 5-HETE was equally effective in inducing lipid body formation in both wild-type and 5-LO genetically deficient mice. Both PAF- and 5(S)-HETE-induced lipid body formation were inhibited by protein kinase C (PKC) inhibitors staurosporine and chelerythrine, the phospholipase C (PLC) inhibitors D609 and U-73122, and by actinomycin D and cycloheximide. Prior stimulation of human PMN with PAF to form lipid bodies enhanced eicosanoid production in response to submaximal stimulation with the calcium ionophore A23187; and the levels of both prostaglandin (PG) E2 and LTB4 correlated with the number of lipid bodies. Furthermore, pretreatment of cells with actinomycin D or cycloheximide inhibited not only the induction of lipid body formation by PAF, but also the PAF-induced "priming" for enhanced PGE2 and LTB4 in PMN. Thus, the compartmentalization of lipids to form lipid bodies in PMN is dependent on specific cellular responses that can be PAF receptor mediated, involves signaling through 5-LO to form 5-HETE and then through PKC and PLC, and requires new protein synthesis. Since increases in lipid body numbers correlated with priming for enhanced PGE2 and LTB4 production in PMN, the induction of lipid bodies may have a role in the formation of eicosanoid mediators by leukocytes involved in inflammation.
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PMID:Mechanisms of platelet-activating factor-induced lipid body formation: requisite roles for 5-lipoxygenase and de novo protein synthesis in the compartmentalization of neutrophil lipids. 866 9

Preliminary ligand binding studies demonstrated that the membrane preparations of the rabbit nonpigmented ciliary epithelial cell line have 3H-prostaglandin E2 binding sites. The binding sites were specific for 3H-prostaglandin E2 as demonstrated by competition with unlabeled prostaglandin E2. The IC50 of prostaglandin E2 for the inhibition of 3H-prostaglandin E2 binding was 435 nM. The stimulation of adenylyl cyclase and phospholipase C by prostanoid receptor agonists, in rabbit non-pigmented ciliary epithelial cells resulted in the formation of either cyclic AMP or inositol phosphates. Prostaglandin E2 and 16-16-dimethyl prostaglandin E2 (both are EP1, EP2, EP3 and EP4 receptor agonists). 11-deoxy prostaglandin E1 (EP2, EP3 and EP4 receptor agonist), butaprost (EP2 receptor agonist), and prostaglandin D2 (DP receptor agonist) stimulated the formation of cyclic AMP in a dose-dependent manner. Maximal stimulation occurred between 1.25 and 2.5 microM for prostaglandin E2 and 16,16-dimethyl prostaglandin E2 and between 10 and 20 microM for 11-deoxy prostaglandin E1 and prostaglandin D2. Prostaglandin E2 and 16,16-dimethyl prostaglandin E2 were more potent (EC50 of 0.25 microM and 0.42 microM respectively) than 11-deoxy prostaglandin E1, butaprost or prostaglandin D2. The formation of cyclic AMP by prostaglandin D2 was inhibited by BW868C, a highly selective DP receptor antagonist. 17-phenyl trinor prostaglandin E2, prostaglandin F2 alpha and U46619, the EP1, FP and TP receptor agonists, respectively stimulated phospholipase C (as measured by the formation of total inositol phosphates) in a dose-dependent manner. The agonists 11-deoxy prostaglandin E1 and butaprost coupled to adenylyl cyclase via guanine nucleotide binding protein, G8, did not increase the turnover of inositol phosphates. The results of the present study suggest that rabbit non-pigmented ciliary epithelial cells express EP1, EP2, DP, FP and TP receptors.
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PMID:Identification of prostanoid receptors in rabbit non-pigmented ciliary epithelial cells. 875 17

Incubation of rat renal mesangial cells with platelet-derived growth factor (PDGF) -AB or -BB led to a transient increase in prostaglandin G/H synthase-2 (PGHS-2) mRNA expression with a maximum after two hours. Expression of PGHS-1 mRNA remained unchanged during short term incubation, but was enhanced about twofold after 8 to 12 hours incubation with PDGF-AB or -BB. Enhanced PGHS activity was still observed after 24 hours. Nevertheless, PGE2 release from mesangial cells was not enhanced by PDGF, hinting to the availability of arachidonic acid as rate-limiting step. PDGF receptors are coupled to multiple signaling pathways, among them phospholipase C gamma PDGF-BB rapidly phoshorylated PLC gamma, while phosphorylation by PDGF-AB was barely detectable. The differential effect of PDGF-BB and PDGF-AB was also seen with respect to calcium signaling: PDGF-BB but not PDGF-AB induced release of Ca2+ from internal stores. Activation of PLC and the resulting transient release of Ca2+ were not considered to be essential for PGHS-2 mRNA induction as both PDGF isoforms were equally effective in mRNA induction. Both PDGF isoforms led to a Ca2+ influx resulting in a long lasting elevation of [Ca2+]i. Enhanced [Ca2+]i seemed to be related to PGHS-2 mRNA expression, because PDGF-induced PGHS-2 mRNA was significantly reduced under Ca2+ free conditions. Diacylglycerol, liberated by PLC, is an activator of protein kinase C (PKC). Down-regulation of PKC by overnight incubation with phorbol ester (0.1 microM) attenuated PGHS-2 mRNA induction by PDGF-AB and -BB. Involvement of PKC was substantiated by the PKC inhibitor H7, which interfered with PDGF-mediated PGHS-2 mRNA expression, while HA1004, a considerably specific inhibitor of protein kinases A and G, was without effect. Taken together, signaling pathways other than PLC gamma seem to be involved in activation of PKC and elevation of [Ca2+]i, which were shown to be essential elements of PDGF-mediated induction of PGHS-2 mRNA expression in mesangial cells.
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PMID:Regulation of platelet-derived growth factor isoform-mediated expression of prostaglandin G/H synthase in mesangial cells. 880 74

Recent studies have shown that macrophages and their functions can be altered by dietary fat. Specifically, diets that are rich in n-3 fatty acids such as fish oils can have significant effects on macrophage cytolytic capacity and the production of select cytokines. The purpose of these studies was to characterize how dietary fish oils altered macrophage tumoricidal activity and the production of tumor necrosis factor-alpha (TNF-alpha). Dietary menhaden fish oil (MFO) significantly decreased the ability of activated macrophages to kill tumor targets compared with macrophages from mice fed safflower oil (SAF), which is high in n-6 fatty acids. Those macrophages from mice fed MFO were hyporesponsive to interferon-gamma. In addition, macrophages from mice fed MFO produced more TNF-alpha after 24 h activation with lipopolysaccharide compared with macrophages from mice fed SAF. That difference in TNF-alpha production was associated with a differential production of and response to prostaglandin E2. Although there are several possible mechanisms by which dietary fat may alter macrophage function and cytokine production, we have investigated signal transduction. Macrophages from MFO-fed mice had a greater increase in intracellular calcium mobilization after treatment with platelet-activating factor (PAF) than macrophages from mice fed SAF. Those differences may be related to an alteration in the PAF signalling pathway by increasing phospholipase C activity. Thus, dietary n-3 fatty acids may significantly alter macrophage tumoricidal activation and TNF-alpha production through the modulation of PGE2 production and signal transduction.
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PMID:Dietary fish oil modulation of macrophage tumoricidal activity. 885 Feb 18


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