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)

Following incubation with polyclonal activators such as PHA or concanavalin A, human peripheral blood lymphocytes show directional migration towards chemotactic factors such as endotoxin-activated plasma, casein or denatured proteins. This migration is inhibited by treatment of the cells with phospholipase C and sphingomyelinase C, but little affected by proteases or glycosidases. In addition, these lymphocytes migrate towards PHA and other lymphocyte activators when these reagents are used as chemoattractants at concentrations well below their mitogenic doses. They also migrate towards staphylococcal protein A. Migration towards PHA and protein A is reduced by pretreating the lymphocytes with proteases but not with phospholipase C. These results suggest two independent membrane interactions which initiate lymphocyte chemotaxis, one acting directly via the lipid bilayer, the other involving the binding of ligands to membrane proteins.
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PMID:Chemotaxis of mitogen-activated human lymphocytes and the effects of membrane-active enzymes. 95 34

Peripheral lymphocytes treated with phospholipase C (phosphatidylcholine cholin phosphohydrolase E [3.1.4.3]) were examined for their response to mitogen and rosette formations. High levels of phospholipase C (greater than 0.01 unit) showed significant toxic effects on the peripheral lymphocytes as examined by the trypan blue exclusion test. This was attributable to "impurities" in the Cl. perfringens phospholipase C preparation since recovery of the mitogen responses were incomplete after heat inactivation of the enzyme. Active phospholipase C at 0.005 unit significantly (50%) suppressed the PHA response with little or no effect on the PWM stimulation. Similarly, a significant suppression of E rosette formation occurred with phospholipase C (0.005 u) treated lymphocytes. Suppression of similarly treated lymphocytes to EAC rosette was slight. It is suggested that the removal of phosphorylated amines from membrane surfaces affects T-cells more than B-cells and that the use of phospholipase C is a useful means of examining membrane functions of the lymphoid system.
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PMID:Effect of phospholipase C on lymphocyte responses to mitogen. 95 57

Ligation of the TCR on Jurkat T lymphoblastoid cells causes an 1,4,5-inositol trisphosphate-dependent rise in intracellular cytoplasmic calcium that is inhibited by PMA, a potent activator of protein kinase C. Consequently, protein kinase C is widely believed to mediate feedback inhibition of TCR-activated phospholipase C. We have now extended these studies to normal unblasted human CD4+ T lymphocytes, examining the PMA sensitivity of both the TCR complex-mediated release of total inositol-phosphates and the resynthesis of the parent phosphoinositides. In contrast to Jurkat, in which PMA inhibited release of 1,4,5-inositol trisphosphate by 60% and total inositolphosphates by 40% (50% inhibitory concentration, 5.6 nM), normal cells displayed a marked increase in anti-CD3-induced phosphatidylinositol (PI) cycling in the presence of PMA. Both total inositolphosphate release and PI resynthesis were maximally elevated (88% and 342%, respectively) by a PMA concentration that also optimally supported a subsequent proliferative response; the ED50 was at least 11.7-fold lower than that for the inhibitory effect of PMA on breakdown of total Jurkat PI. A PKC nonactivating phorbol ester had no effect. If anti-CD3 was replaced by the mitogenic lectin PHA, PI resynthesis was similarly up-regulated by PMA in these highly purified cells. The PMA up-regulatory phenomenon was not a simple consequence of cell blastogenesis, inasmuch as there was no early effect on the non-signaling-associated phosphatidylethanolamine compartment after CD3 stimulation. Thus, PKC activation appears to accelerate TCR-linked PI metabolism in normal Th cells, in contrast to the feedback inhibitor paradigm observed in Jurkat and other tumor cell systems.
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PMID:A protein kinase C-activating phorbol ester accelerates the T cell antigen receptor-stimulated phosphatidylinositol cycle in normal human CD4+ T cells. 134 21

Decay accelerating factor (DAF) is a cell-surface phosphatidylinositol-anchored protein that protects the cell from inadvertent complement attack by binding to and inactivating C3 and C5 convertases. We have measured DAF on human umbilical vein endothelial cells (HUVEC) by immunoradiometric assay after its removal by phosphatidylinositol-specific phospholipase C or Nonidet P-40 detergent extraction and have previously demonstrated that DAF synthesis can be stimulated by phorbol ester activation of protein kinase C. We now report that although stimulation (4-48 h) of HUVEC with various cytokines, including TNF, IL-1, and IFN-gamma, did not alter DAF levels, wheat germ agglutinin (WGA) (5-50 micrograms/ml), a lectin specific for binding N-acetyl neuraminic acid and N-acetyl glucosamine residues, increased DAF levels fivefold when incubated with HUVEC for 12 to 24 h. The lectins Con A and PHA also stimulated DAF expression twofold, whereas a number of others including Ulex europaeus, Bandeiraea simplicifolia lectin I, and Ricinus communis agglutinin I, which bind to endothelial cells, were inactive. The increase in DAF by WGA was inhibited by N-acetyl glucosamine (10-50 mM) but by neither N-acetyl neuraminic acid nor removal of surface N-acetyl neuraminic acid with neuraminidase. However, succinylated WGA, which has unaltered affinity for N-acetyl glucosamine but not longer binds N-acetyl neuraminic acid, was inactive. These data suggest that the binding of WGA to sugar residues alone is not sufficient to trigger DAF expression and that occupation of additional, specific sites are required. The increase in DAF levels on HUVEC was blocked by inhibitors of RNA and protein synthesis. We conclude that continuous occupation by WGA of specific binding sites on HUVEC triggers events leading to DAF synthesis. This unique, long term stimulation of endothelial cells by lectins may be relevant to cell:cell interactions at the endothelium.
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PMID:Wheat germ agglutinin and other selected lectins increase synthesis of decay-accelerating factor in human endothelial cells. 171 83

We have analyzed the induction and expression of Blast-1 at the mRNA and protein levels and demonstrated its identity with CD48. Blast-1/CD48 is expressed on a wider range of cell types, notably T cells and monocytes, than previously thought, but appears to be restricted to lymphoid and myeloid cells. Resting B and T cells express Blast-1/CD48 molecules at the cell surface; however, they lack the epitope recognized by the 17D6 mAb. Resting B cells express no detectable Blast-1/CD48 mRNA. Induction by EBV infection or stimulation with PMA, IL-4, or PHA results in increased levels of Blast-1/CD48 protein (both 6.28 and 17D6 epitopes) at the cell surface. Detailed analysis of EBV-induced expression revealed that it is due to increased steady-state levels of Blast-1/CD48 mRNA induced by transforming but not nontransforming strains of the virus. Induction by IL-1 beta, ionomycin, or suboptimal levels of PMA plus ionomycin results in increased expression of the 17D6 epitope only. In transfected Cos-7 cells Blast-1/CD48 at the cell surface expresses only the 6.28 epitope, whereas cytoplasmic molecules express both 17D6 and 6.28 epitopes. We suggest that these results are most consistent with the idea that Blast-1/CD48 molecules are complexed at the surface of resting cells and Cos-7 cells, resulting in masking of the 17D6 epitope. Activation causes dissociation of the complex, revealing the 17D6 epitope. The existence of 17D6+6.28- Blast-1/CD48 molecules was demonstrated by immunoprecipitation analysis, which also revealed that, unlike the rest of the molecules, this subset was resistant to digestion with glyosylphosphatidylinositol-specific phospholipase C.
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PMID:Expression of the Blast-1 activation/adhesion molecule and its identification as CD48. 184 79

Ligand-induced activation of T cells results in stimulation of phosphatidylinositol-specific phospholipase C (PI-PLC). A structurally diverse family of PI-PLC isoforms has recently been defined, and more than one isoform is frequently coexpressed in a single cell or tissue, suggesting that different forms may play distinct roles in cellular activation, proliferation, or differentiation. We show here that both PLC-alpha and PLC-gamma are expressed in rat splenic T cells and in Jurkat cells (a human T cell line). Activation of Jurkat cells with the combination of PMA and PHA leads to increased expression of PLC-alpha message and decreased expression of PLC-gamma message after 4 h of stimulation. The increase in PLC-alpha transcripts was detectable at 4 h, maximal at 6 h, and remained elevated for at least 24 h. The decrease in PLC-gamma message was transient, with a maximal effect at 4 h, and a return to basal levels by 6 h. Changes in PI-PLC transcripts were also induced by the combination of PMA and the calcium ionophore, ionomycin. These data demonstrate that the expression of transcripts for PLC-alpha and PLC-gamma can be differentially regulated during a cellular response, and raise the possibility that these two isoforms of PI-PLC subserve distinct functions in T cell activation.
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PMID:Divergent regulation of phospholipase C-alpha and phospholipase C-gamma transcripts during activation of a human T cell line. 203 47

Engagement of the TCR (CD3-Ti) by Ag/MHC, CD3 mAb, or lectin mitogen stimulates the very early tyrosine phosphorylation of several cellular substrates including TCR-zeta. The T cell specific protein-tyrosine kinase (PTK), p56lck, has been implicated in the tyrosine phosphorylation of TCR-zeta. However, the significance of this event with regard to CD3-Ti signal transduction remains unclear. Herein, we have investigated the effect of the selective PTK inhibitor genistein (4',5,7-trihydroxyisoflavone) on cellular events associated with activation via CD3-Ti triggering. Genistein inhibited the T cell PTK, p56lck, in a dose-dependent fashion with an ID50 = 40 microM. Genistein also inhibited CD3 mAb or PHA-induced TCR-zeta chain phosphorylation in intact peripheral blood T cells. Genistein blocked the expression of IL-2 and IL-2R (CD25) in T cells stimulated with PHA/PMA or CD3 mAb/PMA, but did not inhibit the de novo expression of the CD69 early activation Ag, which is induced primarily by a PKC-dependent pathway. IL-2 and CD25 expression induced by calcium ionophore A23187 and PMA was largely refractory to inhibition by genistein, suggesting an effect of the drug on calcium-dependent pathways stimulated via CD3-Ti triggering. In this last regard, genistein partially inhibited the CD3 mAb-induced rise in [Ca2+]i but did not inhibit PHA- or CD3 mAb-induced phosphatidylinositol hydrolysis. Consequently, protein-tyrosine phosphorylation does not appear to be a prerequisite for CD3-Ti-mediated activation of phosphatidylinositol-specific phospholipase C activity and PIP2 hydrolysis. An alternative role for PTK in CD3-Ti signal transduction is suggested.
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PMID:Differential inhibition of T cell receptor signal transduction and early activation events by a selective inhibitor of protein-tyrosine kinase. 217 80

The importance of increases in [Ca2+]i, stimulation of Na+/H+ exchange, and turnover of membrane phospholipids as signals for mitogen-induced activation of human T cells has been reviewed. In the presence of optimal concentrations of lectin and appropriately presented antigen, T cells increase [Ca2+]i, secrete IL2, express IL2 receptors and later divide. An increase in [Ca2+]i is critical for IL2 secretion in contrast to the requirements for IL2 receptor expression and IL2-IL2 receptor interaction. Treatment of T cells with TPA appears to bypass the requirement for an increase in [Ca2+]i for IL2 secretion and cell proliferation, indicating that various mitogens can trigger T cells through both [Ca2+]i-dependent and [Ca2+]i-independent pathways. Influx of Ca2+ from the extracellular milieu appears essential for the induced increase in [Ca2+]i associated with IL2 secretion. These increases in [Ca2+]i, which are correlated with the degree of lymphoproliferation and IL2 secretion, are sensitive to changes in membrane potential. The changes in [Ca2+]i are not mediated by the opening of voltage-gated K+ channels but the nature of the potential-sensitive event remains to be determined. The membrane potential effects may be mediated through the gating of a putative Ca2+ channel or by affecting the inward electrochemical Ca2+ gradient. It is clear that lymphoid cells of both T and B lineage possess a functional Na+/H+ antiport, which plays a central role in the regulation of pHi. It is also generally agreed that the antiport can be stimulated by mitogens, co-mitogens and by agents that induce differentiation. The meaning of this stimulation is not, however, entirely understood. It may be an essential signal or link in the series of events triggered by the binding of ligands to their membrane receptors. Alternatively, it may represent an ancillary event, intended to increase H+ ejection in anticipation of an increased metabolic rate. Finally, a third possible reason for the stimulation of Na+/H+ exchange could be to increase the osmotic content of the cells, inducing cell swelling that may be an early requirement for cellular growth. Indeed, amiloride-sensitive cellular swelling has been detected electronically following treatment of T lymphocytes with TPA (Grinstein et al. 1985a). PHA is a potent activator of phosphatidylinositol hydrolysis. In other cell types, receptors are coupled to phospholipase C by a G protein(s). However, the transducing mechanism in human peripheral blood lymphocytes does not appear to be a pertussis toxin-sensitive G protein(s).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane ion fluxes during activation of human T lymphocytes: role of Ca2+, Na+/H+ exchange and phospholipid turnover. 243 15

Human peripheral blood T cells were stimulated to proliferate when cultured with submitogenic doses of PMA and goat antibodies to 5'-nucleotidase (5'-NT). The degree of proliferation, as measured by [3H]TdR incorporation on day 3, was similar to that achieved by stimulation with PHA. Anti-5'-NT antibodies had no effect on PHA-induced proliferation. Maximal stimulation was achieved with 0.6 to 1.0 ng/ml of PMA and 125 micrograms/ml of IgG isolated from a goat anti-5'-NT antiserum. Both intact IgG and F(ab')2 fragments were stimulatory. IL-2R expression and IL-2 secretion were also induced by anti-5'-NT antibodies and PMA. Anti-5'-NT-induced proliferation was inhibited greater than 95% by a murine anti-IL-2 receptor mAb and required less than 0.3% monocytes. Similar results have been obtained with a murine mAb specific for 5'-NT. As expected, anti-5'-NT antibodies and PMA did not induce the proliferation of ecto-5'-NT-T cells isolated by cell sorting. Pretreatment of total T cells with phosphatidylinositol-specific phospholipase C removed an average of 89% of the 5'-NT activity from the cell surface and also inhibited by 83% the ability of the cells to proliferate in response to anti-5'-NT antibodies and PMA. Thus, the activation signal provided by anti-5'-NT antibodies is apparently transduced, in large part, by a form of the enzyme that is attached to the membrane via glycosyl-phosphatidylinositol linkage. These data suggest that 5'-NT may play a role in lymphocyte activation as has been proposed for other glycosyl-phosphatidylinositol-anchored lymphocyte surface proteins.
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PMID:Antibodies to 5'-nucleotidase (CD73), a glycosyl-phosphatidylinositol-anchored protein, cause human peripheral blood T cells to proliferate. 255 May 43

Resting human T lymphocytes do not express receptors for interleukin-2, but expression is rapidly induced by exposure to PHA. After maximal expression 2-3 days after stimulation, a progressive decline in receptor number is observed. Receptor expression can be augmented by reexposure to PHA. In this study we show that activators of protein kinase C including phorbol diester, phospholipase C, and the diacylglycerol congener diC8 also increase IL-2 receptor expression. Moreover, 5-azacytidine, which inhibits cytosine methyltransferase, and hydroxyurea, which inhibits ribonucleotide reductase, also increased receptor number. These studies demonstrate that IL-2 receptor expression can be altered in vitro, and that IL-2 receptor number, in combination with IL-2 secretion, may contribute to the regulation of IL-2-dependent immune responses.
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PMID:Activators of protein kinase C and 5-azacytidine induce IL-2 receptor expression on human T lymphocytes. 258 Aug 52


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