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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigates further the inhibitory effects of transforming growth factor-beta (TGF-beta) on human T-lymphocyte responses to mitogenic stimulation. T cells were stimulated either with mitogenic concentrations of PHA or with submitogenic concentrations of Con A followed by the addition of IL-2. DNA synthesis ([3H]thymidine incorporation) in both systems was inhibited by 60-69% in the presence of TGF-beta, with maximal reduction occurring on days 4 and 5 of culture. Cell surface expression of transferrin receptor (TfR) and IL-2 receptor-alpha (p55) were inhibited by 20-80% in the Con A/rIL-2 system and 20-45% in the PHA system in the presence of TGF-beta. In addition, mitogen-induced up-regulation of TfR and IL-2R mRNA levels were inhibited by TGF-beta. Finally, we investigated the effect of TGF-beta on the assembly of clathrin monomers into assembled coated pits and vesicles, and essential step in TfR and IL-2R alpha turnover. Stimulation of T cells using either mitogen system resulted in an increase in the level of assembled clathrin, which was almost completely inhibited by TGF-beta. These findings suggest that TGF-beta may act at several sites in mitogen-mediated proliferative pathways to contribute to the inhibition of T-cell proliferation.
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PMID:Transforming growth factor-beta inhibits human T-cell proliferation through multiple targets. 147 83

The calcium ionophore, A23187, when used alone was found to induce proliferation of murine T cells, at concentrations of 0.5-1 mM. This response required the presence of syngeneic splenic adherant cells (SAC) as a source of accessory cells. Interestingly, only CD4+ T cells but not CD8+ T cells or B cells responded to the calcium ionophore by proliferation. The inability of CD8+ T cells or B cells to respond was not related to decreased elevation in the intracellular ionized calcium [Ca2+]i concentration induced by the ionophore, because activated CD4+ T, CD8+ T and B cells all exhibited similar elevation in [Ca2+]i. The inability of CD8+ T cells to respond to calcium ionophore was probably due to insufficient production of autocrine growth factors, such as IL-2, inasmuch as the addition of exogenous IL-2 could completely restore the CD8+ T cell responsiveness. Also, exogenous rIL-1 could partially restore purified T cell response to calcium ionophore, whereas, rIL-6 failed to do so. IL-2, but not IL-4, acted as an autocrine growth factor for T cells responding to the calcium ionophore in the presence of SAC, since, antibodies against IL-2 or IL-2 receptor (IL-2R) but not against IL-4, could inhibit the T cell proliferation. Furthermore, exogenous rIL-2 but not rIL-4 supported the proliferation of T cells to calcium ionophore in the absence of accessory cells. Our results suggest that murine lymphocytes exhibit heterogeneity in their proliferative responsiveness to calcium ionophore and that this may not depend on the early activation signal such as the elevation in [Ca2+]i) induced by the ionophore but may depend on subsequent signals which regulate endogenous growth factor production.
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PMID:Murine lymphocytes exhibit heterogeneity in their proliferative responsiveness to calcium ionophore. 148 6

We have continued our previous study of the inhibitory effects of factor VIII concentrates on IL-2 secretion by T cells. Experiments with an extended range of products confirm our previous conclusion that some but not all low, intermediate and high purity concentrates possess inhibitory activity on IL-2 secretion. The inhibition occurs almost immediately after addition of factor VIII concentrate and it was not possible to adsorb inhibitory activity with activated or non-activated cells; this suggests that the mechanism of inhibition involves interference with early T cell activation events rather than simple blocking of cell surface components by inhibitory molecules. The inhibitory components were shown to reside in different molecular weight fractions of concentrates. A strongly inhibitory component of approximately 200 kD and a minor species of approximately 60 kD were identified in strongly inhibitory concentrates. Some products contained a dialysable inhibitory substance which is most likely a salt as it was also present in some formulation buffers. The proportions of the inhibitory components varied widely between products. We have found that the pattern of inhibition using in vitro systems reflects that observed using a mouse in vivo antigen challenge method. In addition we have shown that the previously reported concentrate mediated inhibition of lectin induced low affinity IL-2 receptor (CD25) is mainly a consequence of diminished IL-2 secretion rather than a 'direct' effect on CD25 expression. Considering the wide variation between products of the same purity group, caution should be exercised in drawing conclusions concerning the immunosuppressive effects of a particular type of concentrate in haemophilia patients from study with only one product from that group.
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PMID:Mechanisms of inhibition of T cell IL-2 secretion by factor VIII concentrates. 148 38

Although IL-2 receptor beta chain (IL-2R beta) expressed in various lymphoid cell lines binds IL-2 with an intermediate affinity, IL-2R beta expressed in fibroblasts is unable to bind IL-2, suggesting that IL-2R beta is on its own not sufficient for generating the intermediate-affinity receptor and that lymphoid-specific regulatory control may be operated to allow IL-2R beta to bind IL-2. In the present study, we observed that human IL-2R beta expressed in a mouse myeloma X63-Ag8.653 (X63) by cDNA transfection did not bind IL-2, while the same IL-2R beta expressed in an IL-6-dependent mouse B cell hybridoma F12-28, which was obtained by cell fusion between X63 and lipopolysaccharide (LPS)-induced lymphoblasts, bound IL-2 with the intermediate affinity. Interestingly, when the human IL-2R beta cDNA-transfected X63 clone, which by itself manifests no IL-2 binding, was fused with LPS-induced lymphoblasts, the resultant hybridomas manifested intermediate-affinity IL-2 binding. The IL-2 binding was specifically inhibited by addition of antihuman IL-2R beta mAb (Mik-beta 1) but not by mAb against mouse IL-2R subunits, indicating that human IL-2R beta was responsible for the IL-2 binding, i.e. non-functional human IL-2R beta in X63 was converted to competent IL-2R beta by complementation with a mouse spleen cell-derived factor(s) through the cell fusion. Cross-linking experiments with [125I]IL-2 revealed the presence of a 61 kDa protein other than IL-2R beta in cells expressing the intermediate-affinity IL-2R.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reconstitution of the intermediate-affinity interleukin-2 receptor by cell fusion. 148 30

The IL-2 receptor complex is minimally composed of two genetically unrelated subunits of relative molecular masses 55 and 75 kDa respectively. Structural information deduced from the cDNA sequences of either subunit have not revealed significant information as to the basis of the mechanisms of IL-2 receptor signal transduction. Nevertheless, IL-2 stimulates the activation of one or more tyrosine kinases requiring the functional participation of the p75 member of the receptor complex. Here we have developed the methods to isolate the receptor complex with an associated tyrosine protein kinase. Extracts of membrane glycoproteins from activated normal human T lymphocytes and cell lines demonstrated catalytic activation of tyrosine kinase activity when stimulated with IL-2. Purification of the receptor complex with biotinylated IL-2 revealed the presence of two dominant phosphotyrosyl-proteins of approximate molecular masses 58 and 97 kDa. Denaturation gel electrophoresis followed by renaturation of proteins associated with the IL-2 receptor complex demonstrated that the 97 kDa protein had catalytic autophosphorylation activity. The results indicate that the 58 and 97 kDa phosphotyrosyl-proteins can be found to co-precipitate with the IL-2 receptor complex and that the 97 kDa protein was demonstrated to have protein kinase activity. The association of such kinases with receptors devoid of catalytic structure may represent a unique paradigm of growth-factor receptor mechanisms.
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PMID:Characterization of a tyrosine kinase activity associated with the high-affinity interleukin 2 receptor complex. 149 23

T cell functions are impaired during defined developmental stages of amphibian metamorphosis (Marx et al., 1987). Here we show, using a fluorescent anti-human IL-2 receptor antibody and flow cytometry, that during these stages, the splenocytes of Xenopus laevis, the South African clawed toad, have a progressively diminished capacity to express IL-2 receptors (IL-2R), after in vitro lectin stimulation. Preincubation with human rIL-2 specifically blocks binding of the anti-IL-2R antibody. Separation of an endogenous ligand bound to the IL-2R leads to a substantial increase in available epitope recognized by the anti-IL-2R antibody when pre- and postmetamorphic splenocytes are employed, but not when splenocytes of the prometamorphic stages are treated similarly. Thus, the cells from the prometamorphic stages are not producing significant quantities of the ligand. Finally, we demonstrate that human rIL-2 is not by itself mitogenic in the toad, but it can act as a co-stimulator of antigen-induced mitogenesis. Thus, an absence of an endogenous ligand (autologous IL-2?), coupled with a reduced capacity to express IL-2 receptors may be responsible for impaired T cell clonal expansion in metamorphosing Xenopus. Inhibition of T cell functions during this period is vital, since adult cells forming within the larval body bear surface proteins not found on larval cells (Flajnik et al., 1986).
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PMID:Impaired T cell functions during amphibian metamorphosis: IL-2 receptor expression and endogenous ligand production. 149 41

We recently demonstrated that IL-2 is produced by reactive T cells in CD25-positive malignant lymphomas (ML). Using in situ hybridization, we investigated IL-6 mRNA expression in these CD25-positive ML. The ML tested included 9 anaplastic large cell lymphomas and 3 B-diffuse large cell lymphomas. Five CD25-negative ML were studied as controls. We show that IL-6 producing cells are present in all these ML. The density of positive cells was heterogeneous from case to case. However 3 cases of CD25-positive ML showed a dramatically higher density of IL-6 producing cells (70, 50, 43 producing cells per 10,000 cells, respectively) as compared to the other 9 cases of CD25-positive ML (mean 6.03 +/- 2.1 per 10,000). Morphological and topographical data suggested that several types of cells including fibroblasts, lymphocytes, macrophages and endothelial cells may synthesize IL-6. A combination of immunohistochemistry and in situ hybridization showed that reactive T cells and endothelial cells express the IL-6 gene whereas CD30-positive ML cells do not express this gene. Previous studies showed that IL-6 was capable to induce IL-2 receptor expression as well as production of IL-2 and stimulation of lymphomatous cells growth. Our present results indicate that the paracrine production of this cytokine may play a role in the proliferation of malignant lymphomas.
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PMID:IL-6 mRNA expression in CD25 positive malignant lymphomas. 149 62

The short-term exposure of peripheral blood mononuclear cells (PBMC) to recombinant human interleukin-2 (rhIL-2) at 37 degrees C leads to the generation of lymphokine-activated killer (LAK) activity similar in magnitude to that obtained by the exposure of PBMC to rhIL-2 continuously for 3-5 days. In order to investigate whether the required signal for LAK induction occurred during the short exposure to rhIL-2 or at a later point in the induction phase, PBMC were exposed to rhIL-2 for 1 h at 4 degrees C and then exposed to a low-pH wash to remove bound IL-2 from its receptor. PBMC treated in such a way showed increased LAK activity and proliferation compared to cells exposed to rhIL-2 alone. Expression of the p55 (alpha) subunit of the IL-2 receptor was also increased. In order to cause the augmentation, a lowering of the pH below 4.0 was necessary, and exposure of PBMC to low pH alone (in the absence of rhIL-2) failed to cause activation. Another relevant feature was a transient increase in the expression of the p75 subunit of the IL-2 receptor (beta chain) immediately following the exposure to low pH and the release of interferon gamma, tumour necrosis factor alpha and IL-6; activation was blocked by the inclusion of neutralising antisera raised against rhIL-2 and interferon gamma, thus demonstrating that the endogenous release of these cytokines is important for activation.
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PMID:The augmentation of lymphokine-activated killer activity following pulsing of human peripheral blood mononuclear cells with recombinant human interleukin-2. 151 61

The biological effects of IL-2 are mediated through high (complex of alpha and beta chain) or intermediate (beta chain) affinity IL-2 receptors. Previously, chimeric proteins composed of IL-2 and Pseudomonas exotoxin (IL-2-PE) were shown to be specifically cytotoxic to cells bearing IL-2 receptors. It has also been shown that IL-2-PE chimeric proteins can abrogate T cell-mediated immune response in vitro. In the current study, we have investigated the effects of IL-2-PE on LAK activity both in vivo and in vitro. We administered either IL-2-PE40 (comprised of IL-2 and 40-kDa portion of PE) or IL-2-PE66 (comprised of IL-2 and 66-kDa molecule of PE) to normal C57BL/6 mice for 3 or 8 days and LAK activity was assessed in various organs of mice. We found that IL-2-PE40 generated LAK activity in various compartments of mice and the level of activity was slightly lower than that observed with an equivalent amount of recombinant (r) IL-2 alone. However, IL-2-PE66 failed to generate LAK activity which would have been induced due to an equivalent concentration of rIL-2. IL-2-PE66 also did not induce LAK activity from the splenocytes during in vitro culture while IL-2-PE40 generated good LAK activity. An equivalent amount of IL-2 also generated potent LAK activity. The suppression of LAK activity by IL-2-PE66 was also evident in cells preactivated with IL-2; however, this inhibition was partial. The suppressive activity of IL-2-PE66 was shown to be mediated through IL-2 receptor interactions as excess amounts of rIL-2 were able to abrogate its effect. Both IL-2 toxins were equivalently cytotoxic to IL-2 receptor-bearing HUT 102 cells and both were able to compete from high and intermediate affinity IL-2 receptors. Taken together, our data indicate that IL-2-PE66 is highly cytotoxic to LAK cells while IL-2-PE40 is less cytotoxic. Thus, data from our study and from other published reports indicate that IL-2-PE66 is more potent immunosuppressive agent than IL-2-PE40.
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PMID:In vitro and in vivo suppression of interleukin-2-activated killer cell activity by chimeric proteins between interleukin-2 and Pseudomonas exotoxin. 151 80

In this study we have evaluated two new immunological parameters, soluble IL-2 receptor (s IL-2 R) and TNF, in 119 patients with female solid neoplasms (47 ovarian and 72 breast cancer). Our data demonstrate that both these markers have mean serum levels in cancer patients higher than in normal population, particularly in ovarian cases. Also the overall positivities were higher in ovarian (68%) than in breast cancer (51%). Finally we observed no relevant differences according to the status of disease in both groups of cancer patients. These preliminary results could suggest the possible usefulness of an immunological monitoring in cancer patients, above all when an immunotherapy with biological responder modifiers is proposed.
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PMID:Tumor necrosis factor and soluble interleukin-2 receptor: two immunological biomarkers in female neoplasms. 151 22


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