Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The early signalling events that may ultimately contribute to the assembly and subsequent activation of the NADPH oxidase in guinea-pig peritoneal eosinophils were investigated in response to leukotriene B4 (LTB4). LTB4 promoted a rapid, transient and receptor-mediated increase in the rate of H2O2 generation that was potentiated by R 59 022, a diradylglycerol (DRG) kinase inhibitor, implicating protein kinase C (PKC) in the genesis of this response. This conclusion was supported by the finding that the PKC inhibitor, Ro 31-8220, attenuated (by about 30%) the peak rate of LTB4-induced H2O2 generation under conditions where the same response evoked by 4 beta-phorbol 12,13-dibutyrate (PDBu) was inhibited by more than 90%. Paradoxically, Ro 31-8220 doubled the amount of H2O2 produced by LTB4 which may relate to the ability of PKC to inhibit cell signalling through phospholipase C (PLC). Indeed, Ro 31-8220 significantly enhanced LTB4-induced Ins(1,4,5)P3 accumulation and the duration of the Ca2+ transient in eosinophils. Experiments designed to assess the relative importance of DRG-mobilizing phospholipases in LTB4-induced oxidase activation indicated that phospholipase D (PLD) did not play a major role. Thus, although H2O2 generation was abolished by butan-1-ol, this was apparently unrelated to the inhibition of PLD, as LTB4 failed to stimulate the formation of Ptd[3H]BuOH in [3H]butan-1-ol-treated eosinophils. Rather, the inhibition was probably due to the ability of butan-1-ol to increase the eosinophil cyclic AMP content. In contrast, Ca(2+)- and PLC-driven mechanisms were implicated in H2O2 generation, as LTB4 elevated the Ins(1,4,5)P3 content and intracellular free Ca2+ concentration in intact cells, and cochelation of extracellular and intracellular Ca2+ significantly attenuated LTB4-induced H2O2 generation. Pretreatment of eosinophils with wortmannin did not affect LTB4-induced H2O2 production at concentrations at which it abolished the respiratory burst evoked by formylmethionyl-leucylphenylalanine in human neutrophils. Collectively, these data suggest that LTB4 activates the NADPH oxidase in eosinophils by PLD- and PtdIns 3-kinase-independent mechanisms that involve Ca2+, PLC and PKC. Furthermore, the activation of additional pathways that do not require Ca2+ is also suggested by the finding that LTB4 evoked a significant respiratory burst in Ca(2+)-depleted cells.
...
PMID:Early signalling events implicated in leukotriene B4-induced activation of the NADPH oxidase in eosinophils: role of Ca2+, protein kinase C and phospholipases C and D. 757 12

Receptors for chemoattractants that direct the migration of phagocytic leukocytes to sites of injury/infection also modulate many other leukocyte functions that are critical to the inflammatory response. These chemoattractant receptors, members of the G protein-coupled heptahelical receptor family, have been classically linked to cell activation via phospholipase C, calcium, and protein kinase C. We show here that activation of the N-formyl peptide chemoattractant receptor stimulates an additional protein kinase C-independent pathway through the Src-related tyrosine kinase, Lyn, in human neutrophils. We demonstrate that activation of Lyn is associated with binding to the Shc adapter protein, which becomes phosphorylated on tyrosine residues. This interaction appears to be mediated via the Shc SH2 domain. Complexes of phosphorylated Lyn and Shc with phosphatidylinositol 3-kinase are rapidly formed in stimulated neutrophils, correlating with phosphatidylinositol 3,4,5-trisphosphate [corrected] formation and cell activation. This signaling pathway involving a Src-related kinase and the Shc adapter protein provides a potential mechanism linking chemoattractant receptors to downstream events involving Rac activation and NADPH oxidase. Regulation of Shc by G protein-coupled receptors may also allow these receptors to modulate the activity of the Ras/mitogen-activated protein kinase cascade.
...
PMID:G protein-coupled chemoattractant receptors regulate Lyn tyrosine kinase.Shc adapter protein signaling complexes. 765 13

We studied a step where tyrosine phosphorylation is involved in a signaling pathway for the activation of the superoxide (O2-)-generating NADPH oxidase using electropermeabilized human neutrophils. The permeabilized cells produced O2- by the addition of a protein tyrosine phosphatase inhibitor, vanadate, as well as N-formyl-methionyl-leucyl-phenylalanine (fMLP) and protein kinase C (PKC) activators such as phorbol myristate acetate (PMA) and L-alpha-1-oleoyl-2-acetoyl-sn-3-glycerol (OAG). The O2- production by the stimulants was completely inhibited by PKC inhibitors such as calphostin C and staurosporine and was not affected by 1% ethanol, a metabolic modulator of phospholipase D (PLD). Furthermore, the O2- production by vanadate and fMLP, but not by OAG and PMA, was inhibited by both an inhibitor of phospholipase C (PLC), neomycin, and an inhibitor of tyrosine kinase, ST-638. These findings suggest that tyrosine phosphorylation is involved in the activation of the oxidase at a step before diacylglycerol formation by PLC, and that PLD may not be involved in the signaling pathway in permeabilized cells.
...
PMID:Tyrosine phosphorylation is involved in the respiratory burst of electropermeabilized human neutrophils at a step before diacylglycerol formation by phospholipase C. 768 14

Challenge of neutrophils with concanavalin A (ConA), formyl-methionyl-leucyl-phenylalanine (FMLP), and phorbol 12-myristate 13-acetate (PMA) induced the tyrosine phosphorylation of several proteins. Among these proteins we have identified two mitogen-activated protein kinase (MAPK) isoforms of 43 kDa (p43 MAPK) and 45 kDa (p45 MAPK) molecular mass. Moreover here we show that: (1) FMLP induced the tyrosine phosphorylation of the p43 MAPK, and ConA that of p45 MAPK, while PMA induced the tyrosine phosphorylation of both p43 and p45 MAPK; all these agonists induced the tyrosine phosphorylation of a 75 kDa protein (p75). (2) With FMLP or ConA as agonists, tyrosine phosphorylations of MAPK and p75 can be involved in the process of NADPH oxidase activation. On the contrary, PMA can activate the respiratory burst independently of these phosphorylations. (3) In Ca(2+)-depleted neutrophils, where phospholipid hydrolysis did not take place, ConA or FMLP did not activate the respiratory burst, but while ConA induced the tyrosine phosphorylation of p45 MAPK and p75, FMLP was not able to phosphorylate p43 MAPK and p75. (4) As previously observed in our laboratory, a double stimulation of Ca(2+)-depleted neutrophils with ConA plus FMLP induced a respiratory burst in the absence of activation of second messengers derived from phospholipase C, D and A2 activity. This respiratory burst was accompanied by tyrosine phosphorylation of both p43 and p45 MAPKs. These results indicate that when FMLP is the agonist, both the tyrosine phosphorylation of p43 MAPK and p75, and the activation of NADPH oxidase, are coupled to Ca(2+)-dependent mechanisms. On the contrary, ConA can induce the tyrosine phosphorylation of p45 MAPK and p75 independently of calcium, but an unknown Ca(2+)-dependent mechanism is necessary for the activation of NADPH oxidase by this agonist. This mechanism could be substituted by the induction of tyrosine phosphorylation of both p43 MAPK and p45 MAPK when Ca(2+)-depleted neutrophils are stimulated with ConA plus FMLP.
...
PMID:Tyrosine phosphorylation and activation of NADPH oxidase in human neutrophils: a possible role for MAP kinases and for a 75 kDa protein. 894 67

Platelets primed by exposure to subthreshold concentrations of arachidonic acid or collagen are known to be activated by nanomolar levels of hydrogen peroxide. We here demonstrate that this effect is mediated by hydroxyl radicals (OHzero) formed in an extracellular Fenton-like reaction. H2O2-induced platelet aggregation, serotonin release and thromboxane A2 productions were inhibited by OHzero scavengers and by the iron chelator desferrioxamine; hydroxyl radicals were detected directly by ESR measurements of the spin-trapped OHzero adduct. The role of OHzero was confirmed in experiments with exogenously added iron; free or EDTA-bound ferrous iron activated platelets in a process blocked by deoxyribose, mannitol or catalase, whereas ferric iron was without effect unless reductants were included. The activation by OHzero depended on concomitant release of arachidonic acid and was blocked by the phospholipase A2 inhibitors mepacrine and aristolochic acid, and by the Na+/K+ antiporter inhibitor ethylisopropylamiloride. In contrast, neomycin and staurosporin were without effects, indicating that phospholipase C and protein kinase C were not involved in the initial phase of activation. Neither radical formation nor arachidonic acid release was blocked by aspirin. In whole blood aggregation of platelets could be induced by H2O2 generated upon specific stimulation of neutrophils by N-formyl-methionyl-leucyl-phenylalanine; platelet activation and radical formation were blocked by the NADPH oxidase inhibitor diphenyliodonium as well as by catalase and mannitol. These results suggest that reactive oxygen species act as 'second messengers' during the initial phase of the platelet activation process.
...
PMID:Role of hydroxyl radicals in the activation of human platelets. 817 49

Previous studies have shown that intracellular killing of bacteria by monocytes is stimulated by interaction between IgG and Fc gamma receptors (Fc gamma R) in the membrane of these cells. In the present study anti-Fc gamma R monoclonal antibodies (mAb) were used to investigate the relative contributions of the various classes of Fc gamma R to the intracellular killing of Staphylococcus aureus by human monocytes and the biochemical pathways involved. Anti-Fc gamma RI or anti-Fc gamma RII mAb, but not anti-Fc gamma RIII mAb, efficiently stimulated the intracellular killing of bacteria by monocytes. Cross-linking Fc gamma RI or Fc gamma RII, but not Fc gamma RIII, on monocytes with mouse anti-Fc gamma R mAb followed by bridging with F(ab')2 fragments of goat anti-mouse IgG enhanced this process. Since the NADPH oxidase inhibitor diphenyleneiodonium blocked the Fc gamma R-mediated intracellular killing of S. aureus, oxygen-dependent bactericidal mechanisms are most probably involved. Cross-linking Fc gamma RI or Fc gamma RII but not binding of the mAb to the Fc gamma R on monocytes activated phospholipase C, as demonstrated by the increase in the intracellular concentration of inositol-(1,4,5)-triphosphate. The enhanced intracellular killing stimulated by cross-linking Fc gamma R on monocytes was completely blocked by U-73122, an inhibitor of phospholipase C-dependent processes. Protein kinase C activity, but not the rise in the cytosolic free Ca++ concentration or pertussis toxin-sensitive G proteins, is essential for the Fc gamma R-mediated intracellular killing of bacteria by monocytes. Together, these results demonstrate that cross-linking Fc gamma RI or Fc gamma RII is equally effective in stimulating the intracellular killing of bacteria by monocytes and that this stimulation is a phospholipase C-dependent process.
...
PMID:Stimulation of the intracellular killing of Staphylococcus aureus by human monocytes mediated by Fc gamma receptors I and II. 822 59

Bacterial phosphatidylcholine-preferring phospholipase C (PC-PLC) has been recognized as a virulence factor and is implicated in the hemolytic and dermonecrotic properties associated with certain organisms. Moreover, recent data suggest that PC-PLC may be an important component in the signal transduction cascade by contributing to diacylglycerol (DAG) mass via the hydrolysis of phosphatidylcholine (PC). We have previously shown that PC-PLC can inhibit superoxide generation in human polymorphonuclear leukocytes (PMN). We now extend these observations and show that the mechanism of PC-PLC inhibition of superoxide generation is reversible inhibition of the membrane component of the NADPH oxidase (in a cell-free system) accompanied by expected generation of DAG and phosphorylcholine. Addition of PC reversed the effects of the enzyme. Surprisingly, we also found that phosphatidic acid (PA), the hydrolysis product of phospholipase D, was also produced in intact PMN following PC-PLC exposure. Subsequent addition of the agonist N-formylmethionyl-phenylalanine resulted in further PA production. Restoration of PA in cell-free preparations partially restored superoxide generating capability. We conclude that PC-PLC may enhance bacterial virulence by inhibiting superoxide generation by human PMN, and that this effect is due to direct inhibition of the membrane component of the NADPH oxidase.
...
PMID:Bacterial phosphatidylcholine-preferring phospholipase C reversibly inhibits the membrane component of the NADPH oxidase in human polymorphonuclear leukocytes: implications for host defense. 825 55

To investigate a possible role of phospholipase A2 (PLA2) in the respiratory burst in bovine eosinophilic and neutrophilic leukocytes dependent on GTP-binding protein (G-protein), we permeabilized these cells with Staphylococcus aureus alpha-toxin and induced NADPH oxidase activity with the non-hydrolysable GTP analogue GTP[S] or the aluminium tetrafluoro complex AlF4-. Under same experimental conditions, cells responded with different onset times. The onset time for eosinophils was 50-200 s, for neutrophils it was only a few seconds. GTP[S] stimulated in neutrophils only 5% of the respiratory burst compared to eosinophils, whereas AlF4(-)-induced comparable responses (neutrophils 120% of eosinophils). GDP inhibited these responses with an IC50 value of 2.4 mM. Arachidonic acid showed, with the exception of AlF4- stimulated neutrophils, on both stimuli and cell types an enhancing effect (150%) that reached its maximum at 0.1-1 microM. The PLA2 inhibitor 4-bromophenacylbromide reduced the GTP[S]- and AlF4(-)-induced response almost completely (10 microM) and the inhibition was not significantly different for eosinophils and neutrophils (IC50 1-3 microM). If the respiratory burst was reduced with 4-bromophenacylbromide to 1-4% of the original value, 10% of the basal NADPH oxidase activity could be restored by addition of only 20-100 nM arachidonic acid. In addition, the PLA2 activator adriamycin enhanced the response in a dose-dependent manner and in the same order as arachidonic acid did. The results presented above suggest that the respiratory burst may be regulated by different low-molecular-mass and/or heterotrimeric G-proteins and an active role for arachidonic acid or its metabolites in the activation and the maintenance of the direct G-protein-stimulated respiratory burst in bovine eosinophils and neutrophils.
...
PMID:Nanomolar arachidonic acid influences the respiratory burst in eosinophils and neutrophils induced by GTP-binding protein. A comparative study of the respiratory burst in bovine eosinophils and neutrophils. 826 58

In neutrophils, N-formyl-Met-Leu-Phe (FMLP) stimulates a respiratory burst with subsequent generation of superoxide anion (O2-.) by NADPH oxidase. Signal transduction involved in this process includes FMLP receptor stimulation of phosphoinositide hydrolysis with formation of inositol 1,4,5-trisphosphate and diacylglycerol and phosphatidylcholine hydrolysis with formation of phosphatidic acid. Generation of these second messengers would lead to activation of NADPH oxidase and generation of O2-.. Neutrophils from diabetic subjects and normal neutrophils exposed to glucose have diminished ability to activate the respiratory burst in response to various agonists. The mechanism of this suppression remains unknown. We report herein that treatment of neutrophils with 15 and 50 mM glucose significantly suppresses the O2-. formation in response to receptor-mediated stimulation. The decreased O2-. generation is associated with marked inhibition of phospholipase D (PLD) activity, with limited hydrolysis of phosphatidylcholine and formation of phosphatidic acid. Sorbitol (50 mM), a nonmetabolizable sugar with a similar osmotic effect, has no influence on O2-. generation or PLD activation. The 4 beta-phorbol 12-myristate 13-acetate (PMA)-induced O2-. generation as well as PLD activation are unaffected by glucose. Furthermore, the intracellular Ca2+ transient in response to FMLP is not influenced by glucose. Taken together, these data suggest that glucose differentially interferes with activation of PLD but not phospholipase C. And, the fact that PMA-induced activation of PLD is not altered by glucose further suggests that a protein kinase C independent step leading to the activation of PLD may be altered by glucose.
...
PMID:Glucose suppresses superoxide generation in normal neutrophils: interference in phospholipase D activation. 838 32

The purpose of these studies was to examine the sensitivity of the PIP 2-PLC-transducing pathway (GPLC) and its relationship to the respiratory burst in human polymorphonuclear leukocytes (PMN) stimulated by IL-8, TNF-alpha, or IL-1 beta during sequential changes in buffer oxygen tension from normoxia (pO2 = 180-200 mm Hg), to hypoxia (pO2 < 30 mm Hg) and then reoxygenation (pO2 > 140 mm Hg). Our specific hypothesis was that altered oxygen tensions would regulate the G PLC pathway in human PMN. G PLC activity was assayed by investigating phospholipase C activity by measuring inositol phosphates and diacylglycerol (DAG) formation. Respiratory burst activity was assayed as O 2 production and NADPH oxidase activation in intact PMN and in a cell-free system, respectively, and correlated separately to both early and late DAG production. At 1 min, DAG formation during normoxia was decreased by IL-8 plus fibronectin while hypoxia had no regulatory effect on control of DAG formation by any of the cytokines. In contrast to early DAG formation, hypoxia significantly downregulated late DAG formation induced by buffer without fibronectin, IL-8 plus fibronectin, and IL-1 beta with or without fibronectin. Hypoxia/reoxygenation in and of itself significantly increased DAG formation vs levels seen in the presence or absence of IL-8, TNF-alpha, or IL-1 beta with or without fibronectin. Changes in early DAG production during the alterations in oxygen tension correlated best with corresponding changes in O 2 production in intact cells, whereas late DAG production correlated best with NADPH oxidase activation assayed in the cell-free system. Thus, changes in oxygen tension can directly modulate the extent of the PMN response to stimulation by IL-8, TNF-alpha, or IL-1 beta and the G PLC-receptor pathway is particularly regulated by physiologically relevant periods of hypoxia/reoxygenation.
...
PMID:Altered oxygen tension modulates cytokine-induced signal transduction in polymorphonuclear leukocytes: regulation of the G PLC pathway. 860 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---