Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the nature of cytoplasmic signal transduction pathways in cord blood T cells by stimulating them with tumor promoter (TPA) and calcium ionophore (A23187). Costimulation of T cells with TPA and A23187 induced optimal proliferative responses on Day 2 in cord T cells but on Day 4 in adult T cells. The maximal responses observed in cord T cells were much less than those of adult T cells, whereas the Con A-induced proliferative responses of these cells showed no significant differences. The reduced responses of cord T cells were due to their lower efficiency in activating the cellular events in T cell activation and proliferation phase, because cord T cells have significantly less ability than adult T cells to express IL-2 receptor as well as HLA-DR and produce IL-2 molecules, thereby inducing proliferation. These data show immature characteristics of intracellular signal transduction pathways in cord T cells, which are directly related with the functional immaturity of cord T cells.
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PMID:Demonstration of functional immaturity of signal transduction pathways in human cord T cells. 251 Sep 37

It has been suggested that reserpine blocks expression of delayed hypersensitivity (DH) reactions by depleting tissue mast cells of serotonin, thereby preventing a T cell-dependent release of mast cell serotonin necessary to localize and to amplify the DH response. However, reserpine blocks expression of DH in mast cell-deficient mice. Recently, we showed that the ability of reserpine to interfere with the expression of contact sensitivity was independent of an effect on mast cells, but reflected an effort of the drug on effector T cell function. In the present study we evaluated the mechanisms by which reserpine abrogates the expression of T cell functions. By using human peripheral blood mononuclear cells or enriched T cell populations we found that the drug inhibited, in a dose-dependent fashion, the proliferation of T cells after mitogen stimulation. Reserpine also interfered with the mitogen-induced IL-2 production by these cells, but the IL-2 receptor expression, as measured by immunofluorescence, was unaffected. Despite this, in the continuous presence of reserpine, exogenous IL-2 did not bypass reserpine inhibition of PHA-induced proliferation. By using the fluorescent indicator quin-2 we have demonstrated that preincubation with reserpine prevented the increase of cytosolic free calcium, which accompanies PHA-induced proliferative responses of human T lymphocytes. These results identify the sites of action of reserpine in human T lymphocytes and are sufficient to explain its ability to block cell-mediated immune responses in vitro and in vivo.
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PMID:Characterization of the interference of T cell activation by reserpine. 251 Sep 39

We have previously established that oxidative phenomena are involved in human T-cell activation (Sekkat, Dornand & Gerber, 1988). In the present work we have studied the effect of different anti-oxidants (scavengers of O2-, .OH and lipo-oxygenase inhibitors) on the stimulation of murine T cells. We report here that all the anti-oxidants used suppressed T-lymphocyte proliferation and IL-2 synthesis, the former effect resulting very likely from the latter. This inhibition was concomitant with the triggering of activation. We also demonstrate that the various anti-oxidants have different biochemical targets. Unlike the other compounds, the phenolic drugs nordihydroguaiaretic acid (NDGA) and butylated hydroxyanisole (BHA), which block lipid peroxidation, affect both signals triggered by the binding of lectin to its receptors: they suppress the rise of intracellular free calcium concentration and inhibit some of the events, depending on the sole protein kinase C activation, namely IL-2 receptor expression and phorbol myristate acetate (PMA)-induced pH change. Our results are discussed within the framework of a possible involvement of reactive oxygen species and of arachidonic acid derivative(s) in T-cell activation and IL-2 production.
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PMID:Inhibition of murine T-cell responses by anti-oxidants: the targets of lipo-oxygenase pathway inhibitors. 251 49

A serum factor, believed to be an IgG autoantibody, in certain patients with lepromatous leprosy inhibits the proliferation of mitogen-stimulated lymphocytes. To investigate which stage of the cell cycle was inhibited, we examined the effect of these sera on the kinetics of lymphocyte activation induced by several mitogenic agents: phytohaemagglutinin (PHA), the calcium ionophore A23187, the phorbol ester phorbol myristate acetate (PMA) and purified protein derivative of BCG (PPD). Seven out of 54 sera tested were found to inhibit PHA-stimulated proliferation. Inhibitory sera and to a lesser extent serum IgG from leprosy patients were capable of suppressing the increase in free cytosolic calcium normally observed immediately after PHA stimulation. Subsequent stages of the cell cycle, increase in cell size, the expression of the IL-2 receptor and increase in DNA were also suppressed. The inhibitory sera was not toxic and, if addition of the sera was delayed, would not inhibit lymphocytes that had already entered the cell cycle. Using mitogenic agents which act intracellularly, the normal early increase in cell size with A23187- and PMA-stimulated lymphocytes was not affected by inhibitory leprosy sera or serum IgG, but all subsequent steps in the cell cycle were suppressed; although the inhibition of proliferation in PMA-stimulated cultures was incomplete. The mechanism of action of the inhibitory sera and derived IgG, although acting through a cell surface antigen, appears to interfere with a fundamental process in activation since the effect was seen with all of the diverse stimuli examined in this study.
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PMID:Suppress of the increase in free cytosolic calcium during the inhibition of T-cell activation by an autoantibody present in the serum of leprosy patients. 259 10

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

Purified T cells from rhesus monkeys, like human T cells, do not show a significant mitogenic response to lectins or PMA, but when combined with PMA or accessory cells, PHA and Con A induce a vigorous mitogenic response. This response is strongly impaired in purified T cells from old rhesus monkeys compared to young T cells, from 56 to 72%, and parallels results obtained with T cell preparations containing accessory cells. Likewise, purified T cells do not respond to interleukin 2 (IL-2) or IL-4, but in the presence of PMA, a significant mitogenic response occurs in the young but not the old T cells. This response is augmented by accessory cells, but is still very deficient in the old T cells. These results show that the IL-2 independent activation of T cells triggered by IL-4, like the conventional IL-2 activation, is age impaired. The deficient response to IL-2 implies an age-related deficiency in IL-2 receptor as well in aged rhesus T cells, and may account for the less effective response of the old cells to calcium ionophore (+PMA) activation. The use of purified T cells in these studies obviate the influence of accessory cells, and thus simplify interpretation.
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PMID:Comparison of mitogenic responses of young and old rhesus monkey T cells to lectins and interleukins 2 and 4. 278 61

The effects of the alkaline earth divalent cation Barium (Ba2+) were studied in in-vitro murine polyclonal T cell activation induced with a panel of T cell mitogens consisting of the plant mitogens concanavalin A (ConA), jacalin and phytohaemagglutinin (PHA), a mitogenic anti-Thy1 monoclonal antibody (MoAb), and an anti-murine CD3 MoAb combined with phorbol ester. All modes of T cell activation, except PHA-induced mitogenesis, were blocked in a reversible and dose-related manner by Ba2+. Blockade was evident only if Ba2+ was added within the first 6 h of stimulation, was totally reversed in a competitive fashion by addition of Ca2+ to the medium, and selectively affected interleukin 2 (IL-2) production, without interfering with expression of IL-2 receptor light chains, nor with late IL-2-dependent activated T cell growth. On the other hand, PHA-induced responses stimulated by optimal mitogen doses were resistant to the effects of Ba2+. Ba2+-resistance of PHA responses was due to IL-2-dependent activation and growth of a Ba2+-resistant T cell subset since: (i) limiting dilution analysis demonstrated that this PHA response had a much lower precursor cell frequency than control PHA responses; (ii) proliferation was blocked by anti-IL2 agents, such as cyclosporin A and anti-IL-2 receptor light chain MoAbs, which were much less effective in blocking control PHA responses. Thus, pharmacological use of Ba2+ reveals the existence of a pathway of T cell activation, induced by PHA, with differential interleukin requirements.
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PMID:Functional heterogeneity in the process of T lymphocyte activation; barium blocks several modes of T cell activation, but spares a functionally unique subset of PHA-activable T cells. 278 51

Ca2+/phospholipid-dependent kinase activity (C-kinase) plays an important second messenger role in T lymphocyte responses initiated by the cluster of differentiation (CD3) complex and presumably also lectinic receptors. During treatment with submitogenic or mitogenic amounts of phytohemagglutinin, as well as with anti-CD3 monoclonal antibody and 12-O-tetradecanoyl 13-phorbol acetate, the enzyme was intracellularly redistributed between the cytosol and the surface membrane. Submitogenic amounts of lectin and anti-CD3 were ineffective in inducing proliferation unless exogenous interleukin 2 (IL-2) was supplied, implying that even though IL-2 receptors were expressed, additional signals were required for IL-2 production. This would also indicate that there is a direct relationship between activation of C-kinase and expression of IL-2 receptors. The importance of C-kinase was further substantiated by the ability of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H7), a potent inhibitor of this enzyme, to interfere with IL-2 receptor expression and cellular [methyl-3H]thymidine uptake during primary activation. The drug concentration at which these cellular responses were inhibited by 50% was about the same as that which decreased c-kinase activity by 50% in vitro. H7 also prevented anti-CD3-induced translocation in intact cells. This effect may be related to competition with the phosphatidylserine binding site, which is important for membrane attachment. This drug apparently also interferes with the active center of the enzyme as demonstrated by its ability to inhibit Ca2+/phospholipid-independent phosphorylation of protamine sulfate. This additional mode of inhibition may be important in suppressing intact cell responses under circumstances during which the enzyme displacement to the membrane is nonphysiologic in nature, e.g., during treatment with 12-O-tetradecanoyl 13-phorbol acetate.
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PMID:Inhibition of antibodies to CD3 surface antigen and phytohemagglutinin-mediated T cellular responses by inhibiting Ca2+/phospholipid-dependent protein kinase activity with the aid of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride. 282 Nov 9

CD3+ WT31- T cells were sorted from peripheral blood of a normal healthy donor by a FACS IV and cloned by limiting dilution in the presence of a phorbol ester (tetradecanoyl phorbol acetate, TPA), calcium ionophore (ionomycin, Io), interleukin-2 (IL-2), allogeneic cells, and phytohemagglutinin (PHA). One of the derived clones, 290-2, was investigated in detail. 290-2 mediated strong natural killer (NK) but not lymphokine-activated killer (LAK) activity. It proliferated in the presence of IL-2 but not IL-4. It carried the surface phenotype CD3+ WT31- CD4weak+ CD8-, CD16-, and Leu 19+. Expression of CD4 was heterogeneous within the clone, since two of three subclones were also CD4weak+ but one was CD4-. NK activity was blocked by monoclonal antibody (moAb) to CD1 1a (LFA1), but not by monoclonal antibody (moAb) to either CD3 or CD4. Northern blotting revealed T-cell receptor (TCR-gamma) but not alpha- or full-length beta-chain mRNA. 290-2 proliferated autonomously when stimulated with a combination of TPA +Io, with PHA or CD3 moAb and autologous B-cell lines (B-LCL) (and this was inhibited by an anti-IL-2 receptor moAb), but not to allogeneic B-LCL or any of the other stimulating agents alone. Unexpectedly, the TPA + Io stimulus which resulted in maximal proliferative responses did not trigger interferon-gamma or granulocyte/macrophage colony-stimulating factor production, although both lymphokines were secreted in the presence of B-LCL + TPA + Io. Proliferative responses were not enhanced by the presence of B-LCL. Thus, activation signals sufficient for autocrine proliferative responses were insufficient for secretion of other lymphokines. Such clones will provide valuable reagents for investigating the biology of the TCR-gamma+ T cell.
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PMID:Different signals for stimulation of proliferation and lymphokine secretion by a CD3+ WT31- cloned cytotoxic lymphocyte. 296 87

Activation of lymphocytes leads to the expression of receptors for the calcitropic hormone calcitriol [1,25(OH)2D3], and calcitriol is a potent inhibitor of interleukin-2 (IL-2) and of lymphocyte proliferation. We used peripheral blood mononuclear cells (PBM) activated in vitro with phytohemagglutinin to study 1) the relationship between 1,25(OH)2D3 receptor expression, IL-2 production, and 1,25(OH)2D3-induced inhibition of PBM proliferation in connection with the cell cycle; 2) the effect of 1,25(OH)2D3 on PBM activation and on the expression of activation-related molecules including the IL-2 receptor, and 3) the role of calcium in the antiproliferative effect of the hormone. 1,25(OH)2D3 receptor expression occurred when PBM entered the G1a phase of the cell cycle. The concentration of the receptor protein reached a peak at G1b and declined during the S phase. 1,25(OH)2D3 inhibited cell proliferation by blocking PBM at the G1a-G1b border. The antiproliferative effect of calcitriol was not caused by hormonal interference with the calcium-dependent activation process nor with the expression of activation-related molecules including the IL-2 receptor. Moreover, this effect was not influenced by extracellular calcium, suggesting that the hormonal action cannot be due to calcium translocation. These findings support the contention that 1,25(OH)2D3-induced inhibition of PBM proliferation is mediated through selective inhibition of IL-2 production.
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PMID:The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. 301 18


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