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

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

Recombinant human monocyte-derived interleukin-8 (IL-8M), recombinant human endothelium-derived IL-8 (IL-8E), and a recombinant human truncated form of IL-8 (IL-8T) stimulated a time-dependent (t 1/2 approximately 2-3 s) and concentration-dependent (0.1-100 nM) release of azurophil (myeloperoxidase) and specific (vitamin B12 binding protein, gelatinase) granule constituents from cytochalasin B-treated human neutrophils (HNs) wherein IL-8T = IL-8M greater than IL-8E. An increase in the cytosolic free calcium concentration ([Ca2+]i) was greater in IL-8T- than in IL-8M- or IL-8E-activated HNs, and IL-8T was more potent than either IL-8M or IL-8E in sequentially desensitizing the HNs to the effects of the other IL-8 forms. IL-8 induced a time- and concentration-dependent (0.1-100 nM) increase in the production of inositol 1,4,5-trisphosphate (IP3) in HNs. U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17- yl]amino]hexyl]-1H-pyrrole-2,5-dione), a potent inhibitor of phospholipase C-catalyzed events in HNs, suppressed IL-8-triggered IP3 production, increased [Ca2+]i and granule exocytosis in HNs. The membrane-associated activity of the alpha and beta subtypes of protein kinase C was significantly enhanced in IL-8-activated cells.
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PMID:Postreceptor events associated with human neutrophil activation by interleukin-8. 132 42

Escherichia coli hemolysin (Hly) is a proteinaceous pore-forming exotoxin that probably represents a significant virulence factor in E. coli infections. We investigated its influence on human polymorphonuclear neutrophils (PMN), previously identified as highly susceptible targets. Hly provoked rapid secretion of elastase and myeloperoxidase, generation of superoxide, and synthesis of platelet-activating factor (PAF) and lyso-PAF. Concomitantly, marked phosphatidylinositol (PtdIns) hydrolysis with sequential appearance of the inositol-phosphates, inositol-phosphates, inositol triphosphate, diphosphate, and monophosphate, respectively, and formation of diacylglycerol, occurred. The metabolic responses displayed distinct bell-shaped dose dependencies, with maximum events noted at low toxin concentrations of 0.1-0.5 hemolytic units per milliliter. PtdIns hydrolysis and metabolic responses elicited by Hly exceeded those evoked by optimal concentrations of formylmethionyl-leucyl phenylalanine, PAF, leukotriene B4, A23187, or staphylococcal alpha-toxin. The toxin-induced effects were sensitive toward modulators of PMN stimulus transmission pathways (pertussis toxin, the kinase C inhibitor H7, and phorbol myristate acetate "priming"). We conclude that the marked capacity of low doses of Hly to elicit degranulation, respiratory burst, and lipid mediator generation in human PMN probably envolves signal transduction via PtdIns hydrolysis.
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PMID:Escherichia coli hemolysin is a potent inductor of phosphoinositide hydrolysis and related metabolic responses in human neutrophils. 165 43

1-[6-[[17 beta-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]- 1H-pyrrole-2,5-dione (U-73122), an inhibitor of phospholipase C (PLC)-dependent processes in human platelets, was found to be a potent inhibitor of human polymorphonuclear neutrophil (PMN) activation by structurally unrelated receptor-specific agonists. U-73122 caused a time- and concentration-dependent (0.1-1 microM) inhibition of myeloperoxidase and vitamin B12-binding protein release from PMNs exposed to N-formyl-methionyl-leucyl-phenylalanine, recombinant human C5a, leukotriene B4 and platelet-activating factor. Activation of the respiratory burst, as measured by superoxide anion production, in PMNs stimulated with these agonists was also suppressed by U-73122. These data suggested that U-73122 inhibited a component of signal transduction that was common to the mechanisms of action of these stimuli. Production of inositol 1,4,5-trisphosphate and 1,2-diacylglycerol and the rise in the cytosolic free calcium concentration, which are early postreceptor events in PMN activation, were all suppressed in U-73122-treated PMNs stimulated with the agonists. These signal transduction events require activation of PLC. Receptor-coupled activation of PLC in membranes isolated from PMNs was potently inhibited by U-73122. U-73122, however, had no direct effect on PMN protein kinase C activity. 1-[6-[[17 beta-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl] -2,5- pyrrolidine-dione (U-73343), a close analog of U-73122 that does not suppress PLC activity, did not inhibit receptor-specific agonist-induced PMN responsiveness. U-73122, therefore, is a novel reagent that is useful in investigating PLC function in receptor-mediated PMN activation.
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PMID:Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness. 233 54

Phospholipase C from Clostridium perfringens, when injected into a closed loop of the rat small intestine in vivo, caused an increase in the activity of intraluminal N-acetyl-beta-glucosaminidase and mucosal permeability to sodium fluorescein, indicating damage to the mucosa. Phospholipase C also caused an influx of granulocytes (neutrophils) into the mucosa, as shown by the myeloperoxidase activity--a granulocyte neutrophil marker, and increased localized lipid peroxidation. Pretreatment of animals with quinacrine, a known inhibitor of phospholipase A2, prevented the increases in the luminal N-acetyl-beta-glucosaminidase activity, mucosal permeability, malondialdehyde and myeloperoxidase activity after deposition of phospholipase C in the gut lumen. It is concluded that phospholipase C might impair the function of the mucosal barrier and increase the permeability of the gut to undesirable molecules and pathogens. Part of its action may be mediated via phospholipase A2 activation since pretreatment with quinacrine afforded protection.
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PMID:Phospholipase C-mediated intestinal mucosal damage is ameliorated by quinacrine. 255 3

Human polymorphonuclear leucocytes (PMNL) inactivate Clostridium difficile cytotoxin and C. perfringens phospholipase C, but not C. perfringens enterotoxin. Both whole cells and sonicated suspensions possess activity, but mononuclear cell fractions of peripheral blood do not. Antitoxin activity closely correlates with cell concentration. The highest cell concentrations tested completely inactivated C. difficile cytotoxin by 2 min. Sucrose density gradient fractionation of PMNL showed antitoxin activity to be associated with myeloperoxidase, locating it in the primary or azurophil granules. Toxin inactivation was prevented by protease inhibitors suggesting that it is due to one of the neutral proteases present in these granules. PMNL are more active against C. difficile cytotoxin than purified chymotrypsin. PMNL may be a primary defence against certain bacterial exotoxins.
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PMID:Antitoxin activity of human polymorphonuclear leucocytes. 285 49

A luminol-dependent non-opsonized zymosan-induced chemiluminescence method for phagocytes in small quantities of whole blood (40 microliters; final dilution: 1:14) is described. It was characterized with reference to cellular and humoral components, and also applied to isolated neutrophils, eosinophils and monocytes. Normal values for whole blood chemiluminescence and for neutrophils, eosinophils and monocytes are presented. From the chemiluminescence characteristic of distinct phagocytes and their frequency distribution pattern in whole blood, it is concluded that whole blood chemiluminescence has its source predominantly in neutrophils. The question as to the origin of chemiluminescence in phagocytes of whole blood and isolated neutrophils is investigated. The results support the importance of the myeloperoxidase-H2O2-halide system, but also go beyond this. The release of arachidonic acid by phospholipase A2 and of diacylglycerol and inositol trisphosphate by phospholipase C, the metabolism of arachidonic acid by the cyclooxygenase and lipoxygenase pathway, the activation of membrane NADPH oxidase by diacylglycerol and the calcium mobilisation by inositol trisphosphate are necessary for the chemiluminescence reaction. Inhibition of either mechanism suppresses the chemiluminescence response. The interaction of non-opsonized zymosan with plasma opsonins, phagocyte Fc- and complement receptors, respectively, for the initiation of chemiluminescence, was investigated. Non-opsonized zymosan initiates a chemiluminescence response in blood phagocytes in the absence of opsonin from the interaction of the zymosan polysaccharide component glucan with the complement receptor type 3. In the presence of plasma this receptor type also mediates the major chemiluminescence response brought about by the zymosan-coated cleavage products of complement fraction three, iC3b and to a minor degree C3b, while immunoglobulin G-coated zymosan interaction with the Fc-receptor is in this case of minor importance.
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PMID:Mechanisms of non-opsonized zymosan-induced and luminol-enhanced chemiluminescence in whole blood and isolated phagocytes. 344 Aug 57

Immunization with purified and concentrated staphylococcal toxoid leads to the rapid 12-fold rise of the level of anti-alpha-toxin and to the 17-fold rise of the titres of antibodies to extracellular staphylococcal products. At the period of immunization phasic changes in cell-mediated and humoral immunity characteristics, indicative of the state of the nonspecific resistance system, can be observed. These changes consist in the transient suppression of phagocytosis, including a decrease in the activity of intraleukocytic bactericidal systems (myeloperoxidase and cation protein), a decrease in the activity of the complement and the bactericidal activity of the blood serum, which should be taken into account when using this immune preparation for therapy.
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PMID:[Antigen-specific and antigen-nonspecific reactions of the immunity system in vaccination with a purified concentrated staphylococcal anatoxin]. 359 Nov 23

The cell activation inhibitor CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[ b]thiophene-2- carboxamide, monosodium salt] was evaluated for its effects on human neutrophil functions. CI-959 inhibited spontaneous migration and chemotaxis toward N-formyl-methionyl-L-leucyl-L-phenylalanine (fMLP) with 50% inhibition (IC50) values of 3.6 and 3.1 microM, respectively. CI-959 also inhibited superoxide anion generation in response to C5a, fMLP, serum-opsonized zymosan (SOZ), concanavalin A (Con A), and calcium ionophore A23187 with IC50 values of 2.5, 4.7, 14.5, 5.4, and 14.8 microM, respectively. In comparison, CI-959 inhibited myeloperoxidase microM, respectively. In comparison, CI-959 inhibited myeloperoxidase release in response to C5a, fMLP, SOZ, and Con A with IC50 values of 11.6, 16.1, 7.5, and < 1.0 microM, respectively, while inhibiting the response to A23187 by only 5.5% at 100 microM. At concentrations up to 100 microM, CI-959 had no effect on the respiratory burst or degranulation in response to L-alpha-1,2-dioctanoylglycerol (DiC8) or phorbol 12-myristate 13-acetate (PMA). In addition, the compound inhibited leukotriene B4 release stimulated by fMLP and SOZ (IC50 values 4.0 and 2.5 microM, respectively), while having less activity against the A23187-stimulated response (IC50 > 100 microM). These results demonstrate that CI-959 inhibits cellular responses to stimuli that mobilize intracellular calcium. For cellular responses to inophore-mediated calcium influx, only oxygen radical production was inhibited by CI-959. CI-959 was further evaluated for its effects on neutrophil stimulus-response coupling. At 100 microM, CI-959 had no effect on human neutrophil phospholipase C or protein kinase C. CI-959 inhibited fMLP-stimulated intracellular calcium mobilization and calcium influx with IC50 values of 16.7 and 3.1 microM, respectively, and exhibited less potent calmodulin antagonist activity (IC50 = 90.5 microM). These results indicate that CI-959 may exert its stimulus- and response-specific inhibitory effects on neutrophil functions, in part, through inhibition of calcium-regulated signalling mechanisms.
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PMID:Selective regulation of human neutrophil functions by the cell activation inhibitor CI-959. 814 14

Staphylococcus aureus produces a variety of proteins, including alpha-toxin and protein A, that could contribute to corneal tissue damage during keratitis. We examined corneal infections produced by intrastromal injection of four S. aureus strains--three isogenic mutants, one lacking alpha-toxin (Hly- Spa+), one lacking protein A (Hly+ Spa-), and one lacking both alpha-toxin and protein A (Hly- Spa-), and the wild type (Hly+ Spa+)--in a rabbit model of experimental keratitis. Rabbit corneas were injected intrastromally with 100 CFU of one of the four strains, and the eyes were examined by slit lamp biomicroscopy over a 25-h period. Corneal homogenates were used for determination of CFU and neutrophil myeloperoxidase activity at 5-h intervals. All strains had the same logarithmic growth curve from 0 to 10 h postinfection, after which CFU remained constant at 10(7) CFU per cornea. By 15 h postinfection, slit lamp examination scores were significantly higher for eyes infected with Hly+ strains than for Hly(-)-infected eyes. At this time, distinct epithelial erosions were seen in Hly(+)-infected eyes but not in Hly(-)-infected eyes. Myeloperoxidase activity was significantly greater for Hly(+)-infected corneas than for Hly(-)-infected corneas at both 20 and 25 h postinfection. Spa(+)- and Spa(-)-infected eyes showed no differences in slit lamp examination scores or myeloperoxidase activities. These results suggest that alpha-toxin, but not protein A, is a major virulence factor in staphylococcal keratitis, mediating the destruction of corneal tissue in eyes infected with this bacterial pathogen.
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PMID:Corneal virulence of Staphylococcus aureus: roles of alpha-toxin and protein A in pathogenesis. 818 73

Staphylococcus aureus corneal infection results in extensive inflammation and tissue damage. Our previous studies of bacterial mutants have demonstrated a role for alpha-toxin in corneal virulence. This study analyzes, by genetic rescue experiments, the virulence of mutants affecting alpha-toxin and beta-toxin activity and demonstrates the ocular toxicity of these purified staphylococcal proteins. Three types of isogenic mutants were analyzed: (i) mutants specifically deficient in alpha-toxin (Hla) or beta-toxin (Hlb), (ii) a mutant deficient in both Hla and Hlb, and (iii) a regulatory mutant, deficient in the accessory gene regulator (agr), that produces reduced quantities of multiple exoproteins, including alpha- and beta-toxins. Plasmids coding for Hla and Hlb (pDU1212 and pCU1hlb, respectively) were used to restore toxin activity to mutants specifically deficient in each of these toxins. Either corneas were injected intrastromally with logarithmic-phase S. aureus or purified alpha- or beta-toxins were administered to normal eyes. Ocular pathology was evaluated by slit lamp examination and myeloperoxidase activity of infiltrating polymorphonuclear leukocytes. Corneal homogenates were cultured to determine the CFU per cornea. Eyes infected with the wild-type strain developed significantly greater corneal damage than eyes infected with Agr-, Hlb-, or Hla- strains. Epithelial erosions produced by parent strains were not produced by Agr- or Hla- strains. Hlb+ strains, unlike Hlb- strains, caused scleral edema. Plasmid pDU1212 restored corneal virulence to strain DU1090 (Hla-), and plasmid pCU1hlb restored corneal virulence to strain DU5719 (Hlb-). Application of purified alpha-toxin produced corneal epithelial erosions and iritis, while application of beta-toxin caused scleral inflammation. These studies confirm the role of alpha-toxin as a major virulence factor during S. aureus keratitis and implicate beta-toxin, a mediator of edema, as a lesser contributor to ocular damage.
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PMID:Specific roles of alpha-toxin and beta-toxin during Staphylococcus aureus corneal infection. 912 32


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