Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While the role of the group IVA Ca(2+)-dependent cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in arachidonic acid (AA) metabolism has been well documented, that of its paralogue, Ca(2+)-independent group IVC PLA(2) (cPLA(2)gamma), has remained uncertain. Here we show, using a transfection strategy, that cPLA(2)gamma has the ability to increase the spontaneous and stimulus-induced release of cellular fatty acids. The AA released by cPLA(2)gamma was metabolized further to prostaglandin E(2) via cyclo-oxygenase-1 (COX-1) in the immediate response, and via COX-2 in the delayed response. Mutation of the putative catalytic-centre residue Ser(82) abrogated the AA-releasing function of cPLA(2)gamma both in vitro and in vivo. Confocal microscopy revealed that cPLA(2)gamma was distributed in the perinuclear endoplasmic reticulum membranes. Mutating the C-terminal prenylation site of cPLA(2)gamma abrogated its intracellular membrane localization and cellular AA-releasing function, without reducing its enzyme activity in vitro. Our results indicate that cPLA(2)gamma is the second cPLA(2) enzyme that contributes to cellular AA metabolism and phospholipid remodelling under appropriate conditions.
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PMID:Arachidonate release and prostaglandin production by group IVC phospholipase A2 (cytosolic phospholipase A2gamma). 1261 87

Alterations of the host response by tobacco smoke adversely affect the periodontium. In this study, we examined the effects of in vitro acute smoke exposure on changes in m-RNA expression of primary peripheral mononuclear blood cells through microarray analysis. Mononuclear blood cells were isolated from four healthy non-smokers and plated in culture wells. Half of the cells were then exposed to 5 min of tobacco smoke. Fluorescent c-DNA probes were prepared from the linearly amplified m-RNAs for each sample and hybridized to cDNA microarrays representing approximately 30000 human genes. Significant increases or decreases in m-RNA gene expression between non-smoke-exposed and smoke-exposed samples were identified by permutation t-test, as implemented by the Significance Analysis of Microarrays software package. After smoke exposure, the expression of 90 genes with known function was significantly elevated and the expression of 19 genes with known function was significantly depressed. In addition, 18 upregulated and 26 downregulated transcripts were expressed sequence tags with little information available on function. Approximately 20 of the significantly elevated genes had previously been reported in the literature to be associated with periodontal pathogenesis (fold changes in parentheses). These included plasminogen activator (4.4), Heat Shock Protein (Hsp) 40 kD (2.2), thrombomodulin (4.2), cytochrome c (1.8), COX-2 (2.6), interleukin-1a (1.4), chemokine ligand 1 (3.8), cathepsin L (2.0), and calgranulin A (2.1). In addition, several significantly elevated genes not previously reported in the literature may also play a role in periodontal pathogenesis, and thus warrant further investigation. These include Diphtheria toxin receptor (heparin-binding epidermal growth factor-like growth factor) (7.8), Hsp 10 kDa (1.7), Hsp 105 kD (2.1), Hsp 70 kDa (1.6), and mitogen activated protein kinase 3 (1.5). Among the significantly depressed genes that may play a protective or destructive role in periodontal pathogenesis were interferon gamma receptor 2 (0.58) and chemokine receptor 2 (0.24). Our results may be of use in the search for the molecular mechanisms for the adverse effects of tobacco smoke on the host response.
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PMID:Alteration of gene expression profiles of peripheral mononuclear blood cells by tobacco smoke: implications for periodontal diseases. 1467 73

Here we studied the role of phosphoinositide 3-kinase (PI 3-kinase) and mitogen activated protein (MAP) kinase in regulating bradykinin (BK) induced prostaglandin E(2) (PGE(2)) production in human pulmonary artery smooth muscle cells (HPASMC). BK increased PGE(2) in a three step process involving phospholipase A(2) (PLA(2)), cyclooxygenase (COX) and PGE synthase (PGES). BK stimulated PGE(2) release in cultured HPASMC was inhibited by the PI 3-kinase inhibitor LY294002 and the p38 MAP kinase inhibitor SB202190. The inhibitory mechanism used by LY294002 did not involve cytosolic PLA(2) activation or COX-1, COX-2 and PGES protein expression but rather a novel effect on COX enzymatic activity. SB202190 also inhibited COX activity.
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PMID:PI 3-kinase and MAP kinase regulate bradykinin induced prostaglandin E(2) release in human pulmonary artery by modulating COX-2 activity. 1498 93

Increased prostaglandin E(2)(PGE(2)) synthesis involves multiple enzymes and two isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the Hsp90 chaperone, p23, and is reportedly functionally coupled to constitutive PG endoperoxide H synthase-1 (PGHS-1). Microsomal PGES (mPGES), on the other hand, is inducible by proinflammatory cytokines such as IL-1beta. We have studied the cellular localization of both enzyme isoforms in human placenta at term and early gestation (10 weeks). Cytosolic PGES was immunolocalized to the fibroblasts and macrophages in villous stroma, whereas mPGES was localized in the extravillous trophoblasts (EVTs) as well as macrophages in both term and early gestation tissues. Microsomal PGES was also observed in cytotrophoblasts (CTs), but not in syncytiotrophoblasts (STs), in early gestation. Apoptotic early gestational STs were heavily stained with cPGES. We also investigated the cellular localization of cPLA(2)and PGHS-2 in early gestation and at term. Cytosolic PLA(2)was immunolocalized to the stroma and STs at term, but was only observed in CTs in early gestation. PGHS-2, on the other hand, was immunolocalized to both extravillous and STs in early gestation and at term. Our results suggest that mPGES could play a role in trophoblast invasion via its association with EVTs in the basal plate, whereas cPGES could be involved in apoptosis or repair mechanisms.
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PMID:Differential localization of prostaglandin E synthase isoforms in human placental cell types. 1502 17

Recent studies have suggested that dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) may be more beneficial in the treatment of inflammatory diseases in which platelet-leukocyte interaction dominates the underlying inflammatory process, than inhibitors of COX or LO alone. In this study, we examined oxygenated xanthones, shown previously to inhibit platelet and neutrophil activation, with respect to the potency of COX inhibition. 1,3,6,7-Tetrahydroxyxanthone (norathyriol) was the most potent. Norathyriol suppressed thromboxane B(2) (TXB(2)) and leukotriene B(4) (LTB(4)) formation in calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat neutrophils. Norathyriol was 3-4 times more active against LTB(4) formation than against TXB(2) formation (IC(50) about 2.8 vs. 10 microM, respectively). Norathyriol also inhibited prostaglandin D(2) (PGD(2)) formation in A23187-stimulated rat mast cells (IC(50) 3.0+/-1.2 microM) and in arachidonic acid (AA)-activated mast cell lysate. Norathyriol was a more effective inhibitor of 5-LO activity than of COX, as shown also by analyses of enzyme activities in a cell-free system, of COX and 5-LO metabolic capacity in neutrophils and of ex vivo TXB(2) and LTB(4) formation in A23187-stimulated neutrophils. Moreover, norathyriol inhibited COX-2 and 12-LO with IC(50) values (19.6+/-1.5 and 1.2+/-0.1 microM, respectively) similar to those required for the inhibition of COX-1 and 5-LO (16.2+/-1.5 and 1.8+/-0.4 microM, respectively). Inhibition of 15-LO by norathyriol was slightly less active. Norathyriol had no effect on A23187-induced AA release from neutrophils and did not affect phospholipase A(2) (PLA(2)) activity in a cell-free system. These results indicate that norathyriol inhibits the formation of PGs and LTs in neutrophils probably through direct blockade of COX and 5-LO activities. Norathyriol, a single molecule with multiple targets, might provide a potential therapeutic benefit in the treatment of inflammatory diseases.
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PMID:Inhibition of the arachidonic acid cascade by norathyriol via blockade of cyclooxygenase and lipoxygenase activity in neutrophils. 1508 66

Despite the importance of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in the adhesion and diapedesis of monocytes/lymphocytes, little is known about the mechanisms by which it is regulated. We explored the role of a glycosphingolipid, lactosylceramide (LacCer), in modulating PECAM-1 expression and cell adhesion in human monocytes. We observed that LacCer specifically exerted a time-dependent increase in PECAM-1 expression in U-937 cells. Maximal increase in PECAM-1 protein occurred after incubation with LacCer for 60 min. LacCer activated PKCalpha and -epsilon by translocating them from cytosol to membrane. This was accompanied by the activation of phospholipase A(2) (PLA(2)) and the increase of cell adhesion, which were abrogated by chelerythrine chloride, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (GO 6976) (PKC inhibitors). Similarly, bromoenol lactone (a Ca(2+)-independent PLA(2) inhibitor) and methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA(2) and Ca(2+)-independent PLA(2)) inhibited LacCer-induced PLA(2) activity. Bromophenacyl bromide (a PLA(2) inhibitor) abrogated LacCer-induced PECAM-1 expression, and this was bypassed by arachidonic acid. Furthermore, the arachidonate-induced up-regulation of PECAM-1 was abrogated by indomethacin [a cyclooxygenase (COX)-1 and -2 inhibitor] or N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (a COX-2 inhibitor) but not nordihydroguaiaretic acid (a lipoxygenase inhibitor). In sum, PKCalpha/epsilon are the primary targets for the activation of LacCer. Downstream activation of intracellular Ca(2+)-independent PLA(2) and/or cytosolic PLA(2) results in the production of arachidonic acid, which in turn serves as a precursor for prostaglandins that subsequently stimulate PECAM-1 expression and cell adhesion. These findings may be relevant in explaining the role of LacCer in the regulation of PECAM-1 and related pathophysiology.
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PMID:Lactosylceramide recruits PKCalpha/epsilon and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and adhesion to endothelial cells. 1508 46

Phospholipid-derived mediators are implicated in the initiation and progression of human labor and delivery, particularly in relation to infection-induced preterm labor. We previously demonstrated that, in human intrauterine tissues, lipopolysaccharide (LPS)-stimulated nuclear factor-kappaB (NF-kappaB) DNA binding activity, and subsequent cytokine release can be suppressed by sulfasalazine (SASP) concentrations greater than 5 mM. The aim of this study was to elucidate the effect the SASP on secretory type II phospholipase A(2) (PLA(2)), cytosolic PLA(2) (cPLA(2)), cyclooxygenase (COX) isozymes, and subsequent prostaglandin F(2alpha) (PGF(2alpha)) production in human gestational tissues. Human placenta, amnion, and choriodecidua (n = 4-9 separate placentas) were incubated in the presence of SASP (0.1, 1, 5, and/or 10 mM) under either basal or LPS (10 microg/ml) conditions. After 6 h incubation, the tissues were collected and assayed for type II PLA(2) by ELISA and cPLA(2), COX-1, and COX-2 content by Western blotting. The incubation medium was collected and assayed for type II PLA(2) and 13,14-dihydro-15-keto PGF(2alpha) release by ELISA and PGF(2alpha) by RIA. Treatment of placenta, amnion, and choriodecidua with SASP concentrations greater than 5 mM significantly inhibited basal and/or LPS-stimulated type II PLA(2) content and release, 13,14-dihydro-15-keto PGF(2alpha) release, and cPLA(2) protein content (ANOVA, P < 0.05); however, no effect of SASP was observed on basal or LPS-stimulated COX-1 or COX-2 protein. Although no effect of SASP was observed on basal and LPS-stimulated PGF(2alpha) release from placenta and amnion, it significantly increased both basal and LPS-stimulated PGF(2alpha) release from choriodecidua. In addition, SASP concentrations of 5 mM or greater significantly suppressed NF-kappaB DNA binding activity. These data are consistent with the hypothesis that NF-kappaB regulates the expression and release of phospholipase isozymes.
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PMID:Regulation of phospholipase isozymes by nuclear factor-kappaB in human gestational tissues in vitro. 1512 65

We characterized the tracheal and bronchial relaxation caused by proteinase-activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2-knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)) and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides, respectively, caused relaxation in the isolated ddY mouse trachea and main bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E(2)-induced relaxation. Inhibitors of cytosolic Ca(2+)-dependent phospholipase A(2) (PLA), Ca(2+)-independent PLA(2), diacylglycerol lipase, tyrosine kinase, and protein kinase C exhibited no or only minor inhibitory effects on the PAR-mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH(2), caused airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout mice, the peptide effects were absent and the potency of trypsin decreased. Desensitization of PAR-2 and/or PAR-1 greatly suppressed the relaxant effect of trypsin. The bronchial and tracheal tissues displayed distinct sensitivities toward trypsin and the PAR-2-activating peptides. Our data indicate an involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered relaxation of mouse airway tissue, and substantiate a role for PAR-2 in regulating both the trachea and bronchial responsiveness in the mouse lung.
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PMID:Proteinase-activated receptor-2-mediated relaxation in mouse tracheal and bronchial smooth muscle: signal transduction mechanisms and distinct agonist sensitivity. 1519 93

In this paper, we have determined the effect of both muscarinic acetylcholine receptor (mAChR) and exogenous prostaglandin E(2) (PGE(2)) on PGE(2) production and cyclooxygenases (COX) mRNA gene expression on rat cerebral frontal cortex. Carbachol and PGE(2) increase endogenous PGE(2) production and the COX-1 mRNA levels by activation of PLA(2)s. The COX-1 and COX-2 activity participated in the production of PGE(2) triggered by exogenous PGE(2). While in carbachol-PGE(2) only COX-1 activity is affected. The specific inhibition of PGE(2) receptor was able to impair the increase of endogenous PGE(2) production triggered by both carbachol and exogenous PGE(2). These results suggest that carbachol-activation mAChR increased PGE(2) production that in turn interacting with its own receptor triggers an additional production of PGE(2). Both mechanisms appear to occur by using PLA(2) signaling system. This data should be able to contribute to understand the involvement of PGE(2) in normal brain function and its participation in neuroinflammatory processes.
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PMID:Signaling pathways leading to prostaglandin E(2) production by rat cerebral frontal cortex. 1654 60

The small intestinal epithelium is a highly dynamic system continuously renewed by a process involving cell proliferation and differentiation. The intestinal epithelium constitutes a permeability barrier regulating the vectorial transport of ions, water, and solutes. Morphological changes during cell differentiation, as well as changes in the activity of brush-border enzymes and the expression of transport proteins, are well established. However, little is known about the arachidonic acid (AA) cascade underlying epithelial cell differentiation or its role in the development of epithelial barrier function. The main purpose of this study was to examine the activity of the high-molecular-weight phospholipases A(2) (PLA(2)) and cyclooxygenase (COX) pathway during differentiation, with particular emphasis on paracellular permeability. PLA(2) activity, AA release, COX-2 expression, prostaglandin E(2) (PGE(2)) production, and paracellular permeability were studied in preconfluent, confluent, and differentiated Caco-2 cell cultures. Our results show that Caco-2 differentiation induces a decrease in both calcium-independent PLA(2) activity and COX-2 expression and, consequently, a decrease in AA release and PGE(2) synthesis in parallel with a reduction in paracellular permeability. Moreover, the addition of PGE(2) to differentiated cells, at concentrations similar to those detected in nondifferentiated cultures, induces the disruption of epithelial barrier function. These results suggest that AA release by calcium-independent PLA(2), COX-2 expression, and subsequent PGE(2) release are important for the maintenance of paracellular permeability in differentiated Caco-2 cells.
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PMID:Arachidonic acid cascade and epithelial barrier function during Caco-2 cell differentiation. 1658 83


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