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)

Isolated and combined effects of the calcium ionophore A23187 and of the protein kinase C activator phorbol myristate acetate (PMA) on T cell activation parameters were analysed on unprimed Balb/c lymph node T lymphocytes (LNL). High doses of PMA were mitogenic for resting T cells, but non-mitogenic doses of PMA induced T cell proliferation in combination with A23187, which was non-mitogenic by itself. Mitogenesis induced by a combination of A23187 and PMA (A23187/PMA) showed the following characteristics: it was not abolished after extensive depletion of accessory cells; purified L3T4+, but not Lyt2+ T cells responded in the absence of accessory cells; mitogenesis was completely blocked by a mixture of two monoclonal antibodies directed to the murine interleukin 2 (IL-2) receptor (7D4/3C7mAbs); cyclosporin A, dibutyril cyclic AMP, and T cell K+ channel blockers quinine and verapamil all blocked mitogenesis. A marked synergism between A23187 and PMA was noted in induction of T cell enlargement, IL-2 release, and induction of IL-2 responsiveness. No synergism was noted in IL-2 receptor expression, A23187 and PMA being able to induce IL-2 receptors alone. Calcium ionophore induced IL-2 receptor expression, but failed to induce IL-2 release and IL-2 responsiveness. Addition of A23187/PMA to the IL-2-dependent CTL-L clone did not result in cell proliferation. Addition of A23187/PMA to Con A-activated T cell blasts leads to a vigorous proliferative response. This response is blocked by 7D4/3C7 mAbs, indicating a role for endogenously produced IL-2 in this case. The results indicate that T cell mitogenesis by A23187/PMA is IL-2-dependent, and suggest a critical role for protein kinase C in IL-2 release and induction of IL-2 responsiveness. In addition, the data suggest distinct, but co-operative pathways of IL-2 receptor induction, controlled by elevated Ca2+ alone and by protein kinase C. Subsequent intracellular events of T cell activation by A23187/PMA may be quite similar to those triggered by Con A, since both kinds of stimulation are blocked by agents such as cyclosporin A, dbcAMP and K+ channel blockers.
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PMID:Analysis of isolated and combined effects of calcium ionophore and phorbol ester on T lymphocyte activation. 309 19

A bovine papilloma virus-derived vector was used to direct the high level expression in mouse C127 cells of three different cDNAs encoding the human interleukin-2 receptor. These were: the previously described cDNA clone isolated from the T-cell lymphoma, HUT-102; a cDNA clone isolated from mitogen-activated, normal peripheral blood T cells; and an altered version of the HUT-102 receptor in which Ser247, believed to be the site of protein kinase C-mediated phosphorylation, has been changed to an Ala residue. Fluorescence-activated cell-sorting using a monoclonal antibody directed against the human IL-2 receptor was used to derive stable lines of C127 cells expressing from 2-6 X 10(6) IL-2 binding sites per cell. However, all of these receptors bound IL-2 with low affinity.
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PMID:High level stable expression of human interleukin-2 receptors in mouse cells generates only low affinity interleukin-2 binding sites. 309 20

The purpose of these investigations was to compare the immunosuppressive mechanism of cyclosporine (CsA) with those of lipid-soluble local anesthetics and calmodulin antagonists. Chlorpromazine (CPZ) and pentobarbital (PB) both inhibit lymphocyte activation by attenuating sodium and potassium ion potentials. CPZ and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) can also block calcium-dependent activation processes by inhibition of calmodulin and protein kinase C. All four compounds were found to suppress human and murine lymphoproliferation to both alloantigen or mitogen in a dose-dependent and saturable manner. Exogenous interleukin-2 (IL-2) restored mitogenic responsiveness to cultures suppressed using W-7 and CsA, but not to lymphocytes suppressed with either CPZ or PB. Cytofluorographic analysis revealed that the degree of suppression in drug-treated lymphocytes was significantly correlated with the surface expression of receptors for transferrin and interleukin-2. Inhibition of IL-2 activation by PB was demonstrated to result from a blockade of the mitogenic growth factor signal using the IL-2-dependent cell line HT-2. Thus, the mechanism of action of cyclosporine can be differentiated from those of anesthetic immunosuppressants at the level of responsiveness to interleukin-2. The data support the hypothesis that cyclosporine may be an antagonist of calmodulin that selectively blocks early events in T lymphocyte activation leading to IL-2 synthesis, but does not inhibit the expression or function of the IL-2 receptor.
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PMID:Comparison of the immunosuppressive effects of cyclosporine, lipid-soluble anesthetics, and calmodulin antagonists. Response to exogenous interleukin 2. 309 93

Tac antigen, the receptor for human interleukin 2 (IL-2), contains in its intracytoplasmic region a serine residue (Ser-247) that is seemingly the predominant site of protein kinase C-mediated phosphorylation. A number of studies on growth factor receptors have suggested the importance of phosphorylation in receptor structure, function, and regulation. In this study, we generated site-directed mutations in the Tac antigen cDNA to generate mutant receptors in which Ser-247 or Thr-250, a probable site of minor phosphorylation, was replaced with another amino acid that is not accessible to phosphorylation. Study of the expression of these mutant genes in a T-lymphoid cell line has provided no evidence as to the essential role of the above-mentioned residues in determining the degree of receptor affinity, its ability for signal transduction, and phorbol ester-mediated regulation of the receptor. Our results strongly suggest the existence of an IL-2 receptor "complex" in which the Tac antigen is associated with another molecule(s) that is involved in receptor structure, function, and regulation.
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PMID:Intracytoplasmic phosphorylation sites of Tac antigen (p55) are not essential for the conformation, function, and regulation of the human interleukin 2 receptor. 309 87

1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, suppressed interleukin 2 (IL-2) production and IL-2 receptor (IL-2R) expression of the human leukemic T-cell line, Jurkat, induced by 12-O-tetradecanoyl-phorbol-13-acetate and phytohemagglutinin-P. This effect was significant at 5 microM H-7 without loss of cell viability. Such activity was not observed with N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), a potent inhibitor of cGMP- and cAMP-dependent kinases, and a weak inhibitor of Ca2+-phospholipid-dependent protein kinase (protein kinase C). These findings suggest that protein kinase C is more closely associated with IL-2 receptor expression and IL-2 production of T cells than cGMP- or cAMP-dependent kinases. In addition, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin inhibitor, suppressed both IL-2 production and IL-2R expression. Cycrosporin A (Cy A), a potent immunosuppressive drug, markedly inhibited IL-2 production of Jurkat cells whereas it did not affect the IL-2R expression. Thus, the mechanism of action of Cy A appears to differ from that of the protein kinase inhibitor, H-7, and the calmodulin inhibitor, W-7.
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PMID:Inhibitors of IL-2 production and IL-2 receptor expression in human leukemic T-cell line, Jurkat. 310 62

Activation of primary T-lymphocytes (T-cells) is dependent on interactions with the T3/T-cell antigen receptor complex which results in expression of cell surface receptors for the lymphocytotrophic growth factor interleukin-2 (IL-2). In the present communication we have compared the cellular responses to phorbol ester with IL-2-induced cellular responses. Thus, the effect of respective ligand on T-cell growth, the level of expression and composition of two distinct affinity classes of IL-2 receptors, and phosphorylation of an 80,000 mol. wt cellular substrate for the Ca2+-dependent, phospholipid-dependent protein kinase C (PK-C) was analysed. The results demonstrate that only the high affinity IL-2 receptor class is induced by phorbol esters and that both IL-2 and cell surface expression of its high affinity receptor is required for induction of low affinity IL-2 receptors. Moreover, IL-2 receptor signalling seems not to involve activation of PK-C and the results suggest that another intracellular pathway, distinct from the PK-C pathway which induces high affinity IL-2 receptors, is employed in the transmission of IL-2 growth promoting signals.
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PMID:Interleukin-2 versus phorbol-ester-induced cellular events in normal T-lymphocytes. 310 Aug 84

We report here experiments on the analysis of cellular signal transduction in a series of patients with chronic B cell disorders (B cell chronic lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the response of the leukemic cells with primary external signals (interleukin 2 [IL-2] or B cell differentiation factors [BCDF or IL-6]) with their response to secondary inducers (the phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore A23187) that circumvent the first part of the signal transduction pathway by directly activating the key enzyme protein kinase C. One BCDF was synthesized by mitogen-activated peripheral blood B lymphocytes; a second BCDF was constitutively produced by the human bladder carcinoma cell line T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis measured by 3H-uridine uptake, and immunoglobulin production tested by enzyme-linked immunosorbent assay were used as parameters of successful signal transduction. TPA alone and TPA plus A23187 (synergistically) effectively initiated differentiation in all the leukemia cases. Neither IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On the other hand, IL-2 and BCDF produced a substantial differentiation effect on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to respond to direct stimulation of the second messenger pathway (through protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b) the defect in signal transduction appears to be located upstream of protein kinase C (a possible candidate is a G protein); (c) malignant B cells may spontaneously or after treatment with inducers express the IL-2 receptor (Tac antigen) in the absence of a functional differentiating response to IL-2; and (d) signs of proliferation/differentiation in B-CLL samples after incubation with IL-2 or BCDF might be due to contamination of the cell populations with residual normal B cells.
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PMID:Analysis of signal transduction in B chronic lymphocytic leukemia cells. 312 49

Three stimuli were used to compare the signals necessary for interleukin (IL-2) receptor expression and IL-2 production: triggering of the T-cell antigen receptor/CD3 complex (Ti/CD3) by CD3 antibodies, activation of protein kinase C (PKC) by phorbol esters, and elevation of intracellular calcium levels by calcium ionophore. The salient observations were that IL-2 responsiveness, which reflects IL-2 receptor expression, and T-cell proliferation which requires both IL-2 production and IL-2 receptor expression, are not co-ordinately regulated. Firstly, a low threshold of CD3 activation or a brief (1 hr) exposure of T cells to maximal CD3 stimulation is sufficient to induce IL-2 responsiveness, but higher levels of activation for a prolonged period are necessary to ensure a T-cell proliferative response. Secondly, in response to optimal T-cell stimulation there is a short (2-4 day) period of T-cell proliferation followed by a prolonged phase of IL-2 responsiveness (10-14 days). Differences in the kinetics and signalling requirements for IL-2 receptor expression and IL-2 production, regulated at the level of mRNA expression, provide a molecular basis for these observations. A major difference between induction of IL-2 production and IL-2 receptor expression is that the dual signals of calcium and PKC are necessary for IL-2 production, but a sole stimulus of PKC is sufficient for IL-2 receptor expression. Also, a low level stimulation of PKC will induce IL-2 receptor expression but higher levels of PKC stimulation are required for IL-2 production. As a consequence, triggering of a single receptor, namely the Ti/CD3 complex, results in IL-2 responsiveness, but an additional signal that activates PKC is necessary for IL-2 production. These observations suggest that a Ca2+/PKC dual signal model does not explain completely the signal transduction pathways that regulate T-cell growth. Moreover, precise regulatory mechanisms have evolved to control the homeostasis of the autocrine proliferative response of a T-cell population.
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PMID:Autocrine regulation of T-lymphocyte proliferation: differential induction of IL-2 and IL-2 receptor. 326 5

We have investigated interleukin 2 (IL-2)-induced protein phosphorylation in an IL-2 dependent murine cell line by the two-dimensional gel electrophoresis. IL-2 rapidly and markedly induced phosphorylation of a cellular protein distinct from the IL-2 receptor, with a molecular weight of 67,000 daltons and an isoelectric point of 5.8, named pp67. IL-2 dose-responses of pp67 phosphorylation and cell proliferation were well correlated. Phosphoamino acid analysis showed that the phosphorylation site of pp67 was a serine residue. Further, when the cells were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) instead of IL-2, similar increase of pp67 phosphorylation was observed. Such IL-2 dependent protein phosphorylation was also detected in various human IL-2 receptor bearing T cells. Thus we speculate that the phosphorylation of pp67 could be regulated by protein kinase C and it could be a common feature in an early event of the intracellular growth signaling from the IL-2 receptor.
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PMID:Interleukin 2 (IL-2) rapidly induces phosphorylation of a cellular protein, pp67, in an IL-2 dependent murine cell line. 348 73

Sarcoidosis is characterized by the accumulation of activated lymphocytes in the lungs and other organs and by the spontaneous production of the active form of vitamin D, calcitriol. We hypothesized that calcitriol may modulate the responsiveness of human lymphocytes to the relevant biologic mediator, interleukin-2 (IL-2). After culture for 48 h with phytohemagglutinin, human peripheral blood lymphocytes migrated through nitrocellulose filters, secured in microchemotaxis chambers, in response to IL-2. When calcitriol at 1 nM was included in the cultures, the migratory response to IL-2 was completely abrogated. This inhibitory effect was seen despite the fact that cultured lymphocytes continued to express the IL-2 receptor and other activation markers. A similar but more rapid effect could be demonstrated by including calcitriol in the lower well during our 3-h chemokinesis assay. Calcitriol blocked IL-2-induced lymphocyte migration in a dose-dependent fashion. The synthetic noncalcemic vitamin D analogue MC 903 was equally effective in this assay. IL-2-induced migration could also be prevented by the protein kinase C inhibitor H-7, but calcitriol appeared to be at least 1,000 times more potent. Our studies suggest that calcitriol is a potent natural immunomodulator with rapid suppressive effects that may be mediated through protein kinase C. Synthetic analogues such as MC 903 may offer exciting therapeutic opportunities.
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PMID:Calcitriol and its synthetic analogue MC 903 inhibit the interleukin-2-induced migration of human lymphocytes. 776 30


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