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)

We have reported that U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole- 2,5-dione) an inhibitor of phospholipase C-dependent processes in human polymorphonuclear neutrophils (PMN) and platelets, potently suppresses the responsiveness of suspended PMN and platelets to receptor agonists. We demonstrate here that U-73122 caused a concentration-dependent (10-800 nM) inhibition of N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha (TNF alpha), interleukin-8 and phorbol myristate acetate (PMA)-triggered PMN adhesion on fibronectin, fetal bovine serum or keyhole limpet hemocyanincoated microtiter plates. U-73122 also inhibited PMN adherence to and transmigration through TNF-alpha-activated endothelium (IC50 < 50 nM). Further, U-73122 suppressed interleukin-8, N-formylmethionyl-leucyl-phenylalanine and PMA-stimulated up-regulation of the beta 2-integrin, Mac-1 (CD11b/CD18), on the PMN surface (IC50 < 1.3 microM). U-73122 also caused a time-(15-120 min) and concentration-dependent inhibition (IC50 = 25-100 nM) of the N-formyl-methionyl-leucyl-phenylalanine-, TNF alpha- and PMA-elicited adhesion-dependent, oxidative burst, measured as hydrogen peroxide (H2O2) production, in PMN. The CD18-dependent extracellular release of lactoferrin from PMN activated with these stimuli was also suppressed by U-73122. U-73343 (1-[6-[[17 beta-3- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine dione), a close analog of U-73122, did not affect PMN responsiveness.
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PMID:U-73122: a potent inhibitor of human polymorphonuclear neutrophil adhesion on biological surfaces and adhesion-related effector functions. 876 66

We previously showed that a relatively high dose of LPS induced the selective translocation of protein kinase C-beta (PKC-beta) in LPS-responsive mouse macrophages. This result suggested that phosphatidylinositol-specific phospholipase C (PLC) might be activated in the upstream of PKC-beta. Stimulation of C3H/HeN mouse macrophages by LPS induced the characteristic phosphatidylinositol-1,4,5-trisphosphate (IP3) response, that is, a biphasic response consisting of a rapid increase occurring within the first 1 min, and another increase beginning at around 1 min after stimulation. Only the first response was disappeared when cells were treated with a platelet-activating factor receptor antagonist. LPS-inducible TNF-alpha gene activation, however, was not suppressed by the same antagonist, but suppressed by PKC inhibitors. LPS-stimulated macrophage lysates showed tyrosine phosphorylation of some proteins, and the strongest phosphorylation was observed at molecular mass of 140 kDa. The phosphorylation of this protein started at 40 s after LPS stimulation and continued to increase. Anti-PLC-gamma2 Ab seemed to recognize the same protein as the tyrosine-phosphorylated 140-kDa protein. A low dose of LPS (1 ng/ml) could not induce the tyrosine phosphorylation of this protein. Furthermore, LPS induced only the first phase change, but not the second phase increase in LPS-hyporesponsive C3H/HeJ mouse macrophages. These results indicate that the first phase rapid IP3 change, which is also seen in HeJ macrophages, is mediated via a platelet-activating factor receptor, and is not responsible for TNF-alpha production, while the second phase change mediated by a molecule other than CD14 is responsible for PKC-beta translocation and TNF-alpha production. The results also suggest that the later IP3 change is considered to be mediated through a gamma2 type of phosphatidylinositol-specific PLC.
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PMID:Lipopolysaccharide-induced biphasic inositol 1,4,5-trisphosphate response and tyrosine phosphorylation of 140-kilodalton protein in mouse peritoneal macrophages. 901 81

To understand the pathogenesis of vasculitides, we analyzed how cytokine stimulation of HUVEC in vitro activates the cytotoxic capacity of polymorphonuclear (PMN) granulocytes. IL-1beta, IFN-gamma, or TNF-alpha caused highly significant dose and time-dependent HUVEC injury. TNF-alpha-treated HUVEC activated the PMN by means of phospholipase C-related event, since coincubations conferred PMN to react with a rise of cytosolic calcium concentrations, [Ca2+]i. Ab blockade of ICAM-1 on HUVEC inhibited 50 to 70% of the injury induced by these cytokines, whereas a mAb to E-selectin reduced 45 to 65% of IL-1beta- and TNF-alpha-, but not IFN-gamma-induced cytotoxicity. The role of nitric oxide (NO) was of significance since injury induced by each cytokine was reduced by 60 to 87% by specific NO-synthase inhibitors, as well as by scavenging extracellular NO by oxyhemoglobin. In contrast, injury induced by TNF-alpha was inhibited by neither superoxide dismutase or catalase, alpha1-antitrypsin, alpha2-macroglobulin, nor the platelet-activating factor receptor antagonist WEB-2086. Moreover, PMN from a patient with chronic granulomatous disease were fully capable of mediating cytotoxicity. The possibility that IL-8, produced by HUVEC in response to TNF-alpha, mediated activation of PMN was not corroborated since addition of an IL-8-blocking mAb did not modify HUVEC injury. Nonetheless, the IL-8 mAb (but not WEB-2086) blocked the rise of [Ca2+]i. Thus, in this in vitro model of vasculitis, the effect of IL-1beta, IFN-gamma, and TNF-alpha as promotors of cytokine-mediated neutrophil-dependent injury to HUVEC is a process dependent on expression of adhesion molecules and probably associated with NO produced in the system.
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PMID:Cytokine-induced neutrophil-mediated injury of human endothelial cells. 921 11

Human immunodeficiency virus (HIV) infection may cause a dementing illness. HIV-mediated dementia is clinically and pathologically correlated with the infiltration of activated macrophages and elevated levels of tumor necrosis factor (TNF)-alpha, both of which occur in an environment of small numbers of infected cells. We examined the possibility that HIV protein Tat, which is released extracellularly from infected cells, may induce the production of TNF-alpha. Tat induced TNF-alpha mRNA and protein production dose-dependently, primarily in macrophages but also in astrocytic cells. The TNF-alpha induction was NF-kappaB-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF-alpha release was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial cell activation and suggest new therapeutic approaches for HIV dementia.
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PMID:The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases. 927 85

Hexadecylphosphocholine (HePC) is the main representative of a new group of antineoplastic agents, the alkylphosphocholines. Besides remarkable antiproliferative properties on tumor cells in vitro and in vivo, HePC also induces differentiation and inhibits invasive growth of neoplastic cells. Knowledge of the molecular mechanisms by which HePC mediates its biological effects is poor. The observation that analogous substances, the alkyllysophospholipids, may interfere with lipid dependent intracellular signaling suggested similar mechanisms for HePC. We therefore investigated the effects of HePC on phospholipase C (PLC) activation in intact human leukemia cell lines. HePC inhibited fMLP induced phosphatidylinositol-specific PLC activation in HL60 cells and TNF-alpha induced activation of phosphatidylcholine-specific PLC in U937 cells. HePC reduced the number of TNF-alpha receptors on the surface of U937 cells by about 60%. Receptors for fMLP were not affected. Inhibition of TNF-alpha induced PC-PLC activation, however, seemed to be regulated at a post-receptor level as PLC inhibition and receptor occupancy did not correlate.
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PMID:Hexadecylphosphocholine inhibits phosphatidylinositol and phosphatidylcholine phospholipase C in human leukemia cells. 941 18

Two closely related IkappaBalpha kinases as well as the upstream kinase, NIK, which integrates interleukin-1beta (IL-1beta)- and tumor necrosis factor (TNF)-alpha-dependent activation of the transcription factor NF-kappaB have recently been described. However, in this emerging pathway the role of previously identified components of cytokine-induced NF-kappaB activation, namely phosphatidylcholine-specific phospholipase C and protein kinase C, remains unclear. We now show that, in A549 human alveolar epithelial cells, the activation of a stably transfected NF-kappaB-dependent reporter gene by TNF-alpha and IL-1beta is completely blocked by the phosphatidylcholine-specific phospholipase C inhibitor D609 and the protein kinase C inhibitor RO31-8220. However, IL-1beta-induced IkappaBalpha degradation as well as NF-kappaB nuclear translocation and DNA binding, as determined by Western blot and electro-mobility shift assay, respectively, are not affected by these inhibitors. A similar effect, although less pronounced, is observed with the p38 mitogen-activated protein kinase inhibitor SB 203580. On the basis of these data we propose the existence of a second signaling pathway induced by IL-1beta and TNF-alpha that is activated in parallel to the cascade leading to IkappaBalpha degradation and is specifically required for NF-kappaB-dependent transcriptional competency.
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PMID:IkappaBalpha degradation and nuclear factor-kappaB DNA binding are insufficient for interleukin-1beta and tumor necrosis factor-alpha-induced kappaB-dependent transcription. Requirement for an additional activation pathway. 950 55

The vasculature is protected from complement activation by regulatory molecules expressed on endothelial cells. However, complement fixation also occurs on subendothelial extracellular matrix (ECM) in vitro, and is initiated simply by retraction or removal of overlying cells. To investigate mechanisms controlling vascular complement activation, we examined subendothelial ECM for the presence of complement regulatory proteins. Decay-accelerating factor (DAF) was found on both human umbilical vein endothelial cells (HUVEC) and in their ECM; in contrast, membrane cofactor protein was found only on cells. ECM and HUVEC DAF were distinguishable based on several properties. While HUVEC DAF is anchored to cell membranes by a phospholipase C-sensitive glycosylphosphatidylinositol linkage. DAF was removed from ECM only by proteolytic digestion. Cytokines (TNF-alpha, IL-1 beta, IL-4) increased HUVEC DAF expression, but had minimal effect on ECM DAF; in contrast, phorbol 12-myristate 13-acetate (PMA) and wheat germ agglutinin markedly increased DAF on both HUVEC and ECM. The effect of PMA was mediated by activation of protein kinase C. The complement regulatory potential of ECM DAF was assessed by evaluating the effect of DAF-neutralizing antibodies on C3 deposition on HUVEC ECM, as well as on HeLa cell ECM, which had a considerably higher DAF content. DAF blockade enhanced C3 deposition on HeLa ECM, but had no effect on HUVEC ECM. As ECM DAF is likely to be immobile, i.e. able to interact only with C3 convertases forming in the immediate vicinity, its ability to regulate complement activation may be particularly density dependent, and contingent on endothelial-dependent up-regulation.
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PMID:Decay-accelerating factor is a component of subendothelial extracellular matrix in vitro, and is augmented by activation of endothelial protein kinase C. 954 1

Immune mechanisms, including production of pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), play an important role in early atherogenesis. The study of the mechanisms responsible for the increased cytokine production capacity of hypercholesterolemic hosts is therefore crucial for finding new strategies aimed to stop the development of atherosclerosis. We assessed the lipopolysaccharide (LPS)-induced cytokine production of macrophages from low-density lipoproteins (LDL)-receptor knock-out (LDLR-/-) mice, which have a seven- to ninefold higher plasma LDL concentration. Macrophages of LDLR-/- mice produced approximately twofold more IL-1alpha and IL-1beta in response to LPS when compared with macrophages of control mice (LDLR+/+). TNF-alpha synthesis was only slightly increased. Removal of CD14 by phospholipase C treatment of cells decreased cytokine production by 50% (IL-1) to 80% (TNF), but the differences between LDLR-/- and LDLR+/+ remained the same. In contrast, treatment of cells with anti-CD11c monoclonal antibody inhibited the IL-1alpha and IL-1beta production in LDLR-/- mice towards normal values, while no effect could be seen on TNF. In conclusion, LDLR-/- macrophages stimulated with LPS synthesize more IL-1alpha and IL-1beta than controls and this phenomenon is mediated by the CD11c/CD18 receptor.
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PMID:Increased interleukin-1alpha and interleukin-1beta production by macrophages of low-density lipoprotein receptor knock-out mice stimulated with lipopolysaccharide is CD11c/CD18-receptor mediated. 982 12

Tumor necrosis factor (TNF)-alpha, a pluripotent cytokine implicated in the pathogenesis of airway inflammation, has been shown to provoke hypersecretion of mucin by airway epithelial cells in vitro. In this study, we investigated potential signaling pathways mediating TNF-alpha-induced mucin secretion using guinea pig tracheal epithelial (GPTE) cells in air-liquid interface culture. Exogenously applied TNF-alpha (human recombinant) stimulated mucin secretion in a concentration-dependent manner, with maximal effects at 10 to 15 ng/ml (286 to 429 U/ml). The pathway of stimulated secretion appeared to involve generation of intracellular nitric oxide (NO), activation of soluble guanylate cyclase (GC-S), production of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (PKG). TNF-alpha increased production of nitrite and nitrate by GPTE cells; both mucin secretion and cGMP production were attenuated by NG-monomethyl-L-arginine (1 mM), a competitive inhibitor of nitric oxide synthase (NOS), or by the GC-S inhibitor LY83583 (50 microM); and mucin secretion in response to TNF-alpha or to the cGMP analogue dibutyryl cGMP (100 and 500 microM) was attenuated by the specific PKG inhibitor KT5823 (1 microM). Increased mucin secretion and increased cGMP production in response to TNF-alpha both appeared to be mediated by a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC), and by protein kinase C (PKC), since both responses were attenuated by either D609 (10 and 20 microg/ml), a specific PC-PLC inhibitor, or by each of three PKC inhibitors: Calphostin C (0.3 and 0.5 microM), bisindoylmaleimide (GF 109203X, Go 6850; 20 nM), or Ro31-8220 (10 microM). Collectively, the results suggest that TNF-alpha stimulates secretion of mucin by GPTE cells via a mechanism(s) dependent on PC-PLC and PKC, and involving activation of NOS, generation of NO, production of cGMP, and activation of PKG.
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PMID:Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. 1003 Aug 39

Cholera toxin covalently ADP-ribosylates the a subunit of Gs proteins. The modified Gsalpha activates adenylate cyclase and leads to a dramatic increase in intracellular cAMP. The effect of cholera toxin on the production of tumor necrosis factor (TNF-alpha), a critical mediator of toxicity for a number of bacterial and viral infections, has not been examined. Here we show that cholera toxin stimulated human monocytes to secrete TNF-alpha. The subunit A of cholera toxin alone also induced TNF-alpha production, suggesting that TNF-alpha production is mediated through ADP-ribosylation activity of the toxin. Inhibitors of ADP-ribosylation such as 3-aminobenzamide and niacinamide blocked TNF-alpha induction. However, cyclic AMP analogs and adenylate cyclase activator forskolin did not induce TNF-alpha production in monocytes, suggesting that TNF-alpha induction is independent of cAMP. Furthermore, cholera toxin-induced TNF-alpha production was suppressed by protein kinase C inhibitors H7 and sphingosine and by phospholipase C inhibitors U73122 and ET-18-OCH3, suggesting that PLC and PKC mediate TNF-alpha induction. Cholera toxin-mediated induction of TNF-alpha occurs at the transcription level as demonstrated by the time-dependent expression of TNF-alpha mRNA. These results raise the possibility that TNF-alpha may play an important role in cholera toxin-mediated toxicity and demonstrate that cholera toxin activates TNF-alpha production through PLC-dependent and cAMP-independent pathways. The probable mechanisms of signal transduction from cholera toxin to PLC in monocytes will be discussed.
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PMID:Cholera toxin induces tumor necrosis factor alpha production in human monocytes. 1054 36


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