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)

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

Several monoclonal antibodies directed against a number of T cell surface molecules are used to elucidate the role of these molecules (cell surface molecules) in T cell activation. The activation of T cells via these molecules are both antigen-dependent (CD3/TcR complex) and antigen-independent. Irrespective of their antigen dependency, these monoclonal antibodies activate T cells by a classical signal transduction pathway, in which the binding of monoclonal antibodies to their cell surface receptors leads to activation of phospholipase C resulting in the depolarization of plasma membrane, hydrolysis of IP2 and IP3 and DAG, the 'second messengers'. IP3 leads to mobilization of intracellular calcium to contribute to an increase in [Ca++]i, whereas DAG causes activation and translocation of PKC and an increasing apparent affinity for Ca++. The role of IP4 in the mobilization of intracellular calcium is emerging. In addition, influx of extracellular calcium also contributes to increase in [Ca++]i. The increase in [Ca++]i following activation via some T cell surface antigen is predominantly due to intracellular mobilization of Ca++ (e.g. CD3/TcR complex), whereas activation via other T cell surface antigen, the increase in [Ca++]i is almost entirely due to an influx of extracellular calcium (e.g. CD5 antigen). All these molecules activate autocrine system of T cell growth, namely IL-2 production, IL-2 receptor expression and T cell proliferation.
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PMID:Mechanisms of transmembrane signalling in human T cell activation. 269 33

The murine T-lymphoma cell line LBRM-33 is known to require synergistic signals delivered through the antigen receptor (Ti-CD3) complex, together with interleukin 1 (IL-1), for activation of IL-2 gene expression and IL-2 production. Although 12-O-tetradecanoylphorbol-13-acetate (TPA) was capable of replacing IL-1 as an activating stimulus under certain conditions, biologic studies indicated that TPA failed to synergize with Ti-CD3-dependent stimuli under conditions in which IL-1 was clearly active. Acute exposure to TPA and other active phorbol esters resulted in a concentration-dependent inhibition of the increases in phosphoinositide hydrolysis and intracellular free Ca2+ concentration stimulated by phytohemagglutinin or anti-Ti antibodies. TPA treatment induced no direct alteration of phospholipase C enzymatic activities in LBRM-33 cells. In contrast, both Ti-CD3 cross-linkage and TPA rapidly stimulated the phosphorylation of identical CD3 complex polypeptides, presumably via activation of protein kinase C. Exposure of LBRM-33 cells to TPA resulted in a time-dependent, partial down-regulation of surface Ti-CD3 expression. Thus, TPA treatment inhibited the responsiveness of LBRM-33 cells to Ti-CD3-dependent stimuli by inducing an early desensitization of Ti-CD3 receptors, followed by a decrease in membrane receptor expression. These studies indicate that phorbol esters deliver bidirectional signals that both inhibit Ti-CD3-dependent phosphoinositide hydrolysis and augment IL-2 production in LBRM-33 cells.
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PMID:Inhibition of T-cell antigen receptor-mediated transmembrane signaling by protein kinase C activation. 297 23

The cell surface ganglioside GM1 is the specific receptor for the B subunit of cholera toxin. We show here that in the human Jurkat T cell line an increase in intracellular free Ca2+ concentration can be elicited by using B subunits to ligate GM1 molecules. This Ca2+ signaling effect is clearly mediated through GM1 because it can be observed after direct insertion of exogenous GM1 in a Jurkat cell variant deficient in GM1 expression. The observed Ca2+ response clearly involves both the release of Ca2+ from intracellular stores and a Ca2+ influx from extracellular spaces. It is sustained in the presence of 1 mM extracellular Ca2+, whereas it becomes transient in Ca(2+)-free medium. We show that the GM1-mediated stimulation partially empties the CD3-dependent and inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ pool suggesting a dependence of the Ca2+ response from activation of phospholipase C (PLC) metabolism. Accordingly, tyrosine phosphorylation of PLC gamma-1 can be evidenced but only in Jurkat cells highly expressing GM1. GM1 stimulation results in an IL-2 production comparable to that obtained after CD3 activation. Finally, the GM1-linked cell Ca2+ activation pathway is also observed in a Jurkat cell clone lacking Ag-specific receptor expression suggesting that the presence of functional CD3/TCR molecules is not essential for GM1-induced cell Ca2+ response. Altogether, these data show that cell surface gangliosides GM1 may act as a signaling molecule in Jurkat T cells possibly by a new pathway, a finding of importance when considering a possible function for ubiquitous membrane carbohydrate structures in T cell recognition systems.
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PMID:Cell calcium signaling via GM1 cell surface gangliosides in the human Jurkat T cell line. 751 41

Stimulation of B lymphocytes by the cross-linking of surface Ig (sIg) with an F(ab')2 antibody fragment leads to the rapid activation of several tyrosine kinases. This gives rise to the activation of phospholipase C gamma (PLC gamma) and the generation of inositol phosphates. These, in turn, lead to a prolonged elevation of intracellular Ca2+ ([Ca2+]i) consisting of a rapid release of Ca2+ from intracellular stores and a sustained influx of extracellular Ca2+. In contrast, co-cross-linking sIg to Fc gamma receptor (Fc gamma RII) with intact anti-sIg induces a much more transient increase in [Ca2+]i. Stimulation of the murine B cell lymphoma, A20, with F(ab')2 anti-sIgG leads to the production of high levels of IL-2, while co-cross-linking of sIgG with Fc gamma RII blocks this response. In studies reported here, we show that co-cross-linking of Fc gamma RII with sIg prevents the influx of extracellular Ca2+ without significantly affecting the tyrosine phosphorylation of substrates including PLC gamma 1, PLC gamma 2, and Syk or the mobilization of Ca2+ from intracellular stores. In cells that had been previously activated with F(ab')2 anti-IgG, co-cross-linking of sIg to Fc gamma RII rapidly abrogated the influx of extracellular Ca2+ by closing the plasma membrane Ca2+ channel. Additionally, even 2-3 h after stimulation of the cells with F(ab')2 fragment, addition of intact anti-IgG to the cells, or removal of extracellular Ca2+, markedly inhibited (> 90%) IL-2 production. These results indicate that co-cross-linking sIg with Fc gamma RII both prevented the opening of and actively closed the Ca2+ channel, and, through this mechanism, Fc gamma RII was able to control production of IL-2. Overall, since influx of extracellular Ca2+ has been found to be necessary for the proliferation and differentiation of B cells, Fc gamma RII may play a critical role in controlling these responses by regulating the opening of the Ca2+ channel.
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PMID:Cross-linking of Fc gamma receptor to surface immunoglobulin on B cells provides an inhibitory signal that closes the plasma membrane calcium channel. 751 64

CTLL-2 cells are a clone of CTL that are dependent on IL-2 for proliferation. In addition to various cytokine receptors, we observed that these cells express three subtypes of adenosine receptors (ARs). In an initial attempt to delineate the functions of these receptors in CTLL-2 cells, we tested their role in proliferation. Elimination of endogenous adenosine with adenosine deaminase (ADA) markedly suppressed IL-2-dependent proliferation of these cells. This proliferative response was restored by addition of R-phenylisopropyladenosine (R-PIA), a non-hydrolyzable adenosine analogue. The stimulatory response to R-PIA was attenuated following blockade of ARs by 0.5 mM theophylline and 10 microM BW-A1433, but not by blockade of the A1AR with 100 nM xanthine amine congener. The rank order of potency of adenosine analogues in proliferation assays was R-PIA > or = N-ethylcarboxamide adenosine > S-PIA > PAPA-APEC (a substituted ethylamino-5'-N-ethylcarboxamidoadenosine). These data suggest a potential role of the A3AR in the proliferative response. R-PIA stimulates production of 1,4,5-inositol trisphosphate in CTLL-2 cells, suggesting a role of the phospholipase C signaling pathway in the proliferative response. A23187 (100 nM) and phorbol 12,13 dibutyrate (10 nM), but not 4 alpha-phorbol (10 nM), were able to restore IL-2-dependent CTLL-2 proliferation in the presence of ADA. Furthermore, inhibition of protein kinase C by staurosporine (10 nM) and of phospholipase C by tricyclodecan-9-yl-xanthogenate (D609) blocked R-PIA-mediated cell proliferation. These data demonstrate an obligatory role of adenosine in IL-2-dependent proliferation of CTLL-2 cells and support the involvement of an AR-stimulated phospholipase C signaling pathway in this process.
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PMID:Adenosine acts as an endogenous modulator of IL-2-dependent proliferation of cytotoxic T lymphocytes. 767 97

We had previously reported that the CD29 mAb "K20," presented in a soluble form, blocks peripheral T cell proliferation/activation induced by a CD3 mAb. To better characterize the negative signal delivered by soluble K20, we have investigated its effects on the phospholipid metabolism, both in Jurkat and CD4+ T cells. In CD3-activated T cells, K20 inhibited the increase of diacylglycerol (DAG) and phosphatidic acid levels, but did not modify phosphatidylinositol 4,5-bisphosphate levels, cytosolic Ca2+ raise, and inositolphosphates formation, indicating that K20 did not inhibit phosphatidylinositol 4,5-bisphosphate hydrolysis by phospholipase C-gamma. Moreover, in these conditions, K20 increased phosphatidylethanolamine levels, without variation of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol, suggesting that K20 specifically increased the phosphatidylethanolamine biosynthesis from DAG. Thus, the effects of K20 on DAG and phosphatidic acid levels resulted from an accelerated catabolism rather than from a defect of synthesis. That K20 acts solely at an early step of T cell activation, namely before the binding of IL-2 to its receptor, is supported by the observation that adding exogenous rIL-2 increased proliferation in spite of K20. These results suggest that the beta 1 integrin molecules interact with the membrane phospholipid metabolism and they appear to be the hallmark of a peculiar negative pathway of T cell activation, likely to play an important regulatory role mediated via the T cell integrin molecules.
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PMID:Suppressive effect of T cell proliferation via the CD29 molecule. The CD29 mAb 1 "K20" decreases diacylglycerol and phosphatidic acid levels in activated T cells. 768 29

We have characterized the IL-8-induced signal transduction processes in T lymphocytes. A basal level of IL-8 receptor expression was shown on mixed PBL, as identified by using phycoerythrin (PE)-coupled IL-8, and this expression was increased following IL-2 stimulation. Scatchard analysis of T cells revealed competitive binding of IL-8 with a Kd of 0.55 nM, with approximately 1200 receptors per cell, on freshly isolated T cells. After 24 h in culture following purification, reverse transcriptase PCR (RT-PCR) analyses show the mRNA for only the type B IL-8R on these cultured T lymphocytes and the cell line MOLT-4. Stimulation of T lymphocytes or T cell clones with IL-8 led to generation of inositol trisphosphate and calcium flux. In addition, when T cells were prelabeled with [3H]oleic acid, IL-8 caused a long lasting, time- and dose-related increase in [3H]phosphatidylethanol (PtE), indicating activation of phospholipase D (PLD). By contrast, this IL-8-dependent PLD activity was undetectable in IL-8-stimulated neutrophils. PLD activation appeared to be downstream of protein kinase C, because several inhibitors abrogated the increase in [3H]PtE, whereas guanosine-5'-O-(3-thiotriphosphate (GTP(gamma)S) and inositol trisphosphorothioate (IP3S3) both increased the generation of [3H]PtE. Together, these results demonstrate that the IL-8RB receptor is sufficient to mediate phospholipase C (PLC) and PLD activation in T lymphocytes, but not in neutrophils, and indicate an important difference in receptor usage and signal transduction pathways between IL-8-stimulated lymphocytes and neutrophils.
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PMID:IL-8-induced signal transduction in T lymphocytes involves receptor-mediated activation of phospholipases C and D. 770 9

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.
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PMID:Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. 786 38

The presence of specific receptors for gastrointestinal hormones on T cells and their involvement in the immune response are still matters of debate. We reported the effects of gastrin-cholecystokinin (CCK)-related peptides on J.RT3-T3.5 Jurkat cells. A single class of high-affinity binding sites (dissociation constant approximately 0.1 nM) for gastrin and CCK-8 was evident on these cells. These peptides dose-dependently induced a transient increase in intracellular Ca2+ concentration ([Ca2+]i), which was independent of extracellular Ca2-. L-365,260 was 150- to 300-fold more potent than L-364,718 to inhibit radiolabeled ligand binding or peptide-stimulated [Ca2+]i increase, confirming the gastrin-CCK-B nature of the receptor. Gastrin caused a rise in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] level within 5 s of stimulation. Finally, gastrin increased interleukin (IL)-2 secretion in J.RT3-T3.5 cells. We conclude that 1) J.RT3-T3.5 cells possess "gastrin-CCK-B type" receptors coupled to phospholipase C activation, Ins(1,4,5)P3 formation, and Ca2+ release from intracellular Ca2+ pools, and 2) these receptors could be involved in the regulation of IL-2 production.
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PMID:Gastrin-CCK-B type receptors on human T lymphoblastoid Jurkat cells. 790 Aug 13


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