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)

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 macrolide FK-506, like the cyclic undecapeptide cyclosporin A (CsA), is a potent immunosuppressant that interferes with the transcriptional activation of several early-phase genes in T lymphocytes, including that for interleukin-2 (IL-2). We compared the effects of FK-506 and CsA on transcription from the 5' upstream activating sequences (UAS) of the human IL-2 gene and several cellular and viral UAS to define cis-acting sites which may be responsive to FK-506. The UAS surveyed included the human IL-2 receptor alpha-chain, human metallothionein II, simian virus 40 early, human cytomegalovirus immediate-early, adenovirus major late, and Rous sarcoma virus long terminal repeat UAS. In addition, we studied multimers of several defined promoter elements (NFIL-2A, NF-kappa B, or NF-AT1) which are found in the UAS of the human IL-2 gene and which have been reported to be responsive to CsA when linked to a minimal promoter element (TATA box and transcription start site). Each promoter-regulatory region was fused to the bacterial chloramphenicol acetyltransferase gene and used to transiently transfect Jurkat cells. Quantitative chloramphenicol acetyltransferase assay determinations indicated that the transcriptional activity of each UAS induced upon T-cell activation was (i) completely sensitive, (ii) partially sensitive, or (iii) resistant to inhibition by CsA and FK-506. The induced transcription driven by the IL-2 promoter elements NF-AT1 and NFIL-2A could be blocked completely by FK-506 or CsA. Gel mobility shift assays indicated that the binding activities of the factors specifically interacting with these sequences were detected in activated cells regardless of whether the cells were treated with FK-506 or CsA. The results suggest that FK-506 or CsA inhibits a transacting mechanism(s) without disrupting the binding activities of these transcription factors. The degree to which each UAS was resistant to FK-506 was consistent with the level of transcription induced by phorbol myristate acetate, while UAS which were sensitive to inhibition by FK-506 were dependent on the presence of both phorbol myristate acetate and ionomycin.
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PMID:The immunosuppressant FK-506 specifically inhibits mitogen-induced activation of the interleukin-2 promoter and the isolated enhancer elements NFIL-2A and NF-AT1. 171 1

Stable transformants of the Jurkat T-cell line have been obtained that express either of two distinct forms of the type 1 human immunodeficiency virus nef gene: the nef-1-encoded protein (Nef-1) contains alanine, glycine, and valine at positions 15, 29, and 33, respectively; the protein specified by nef-2 (Nef-2) has threonine, arginine, and alanine at the corresponding positions. When Jurkat cells or their Nef-2-expressing transformants are treated with phorbol 12-myristate 13-acetate (PMA) plus either phytohemagglutinin (PHA) or antibodies against CD3 epsilon, T-cell receptor beta chain, or CD2, there is a prompt increase in interleukin 2 (IL-2) mRNA and intracellular calcium and in the IL-2 receptor alpha chain on the cell surface. Although cells expressing Nef-1 also induce calcium mobilization and the production of IL-2 receptor alpha chain, the formation of IL-2 mRNA is blocked in response to these stimuli. Moreover, Nef-1-expressing cells transfected with a plasmid in which the IL-2 promoter is fused to the chloramphenicol acetyltransferase (CAT) gene fail to induce CAT following treatment with PMA and PHA. By contrast, the parental and Nef-2-containing cells induce CAT normally. Nef-1-expressing cells can produce IL-2 mRNA in response to a combination of PMA and ionomycin, although much less efficiently than the parental Jurkat cells or Nef-2-expressing cells. These findings, and others described herein, suggest that the virally encoded Nef protein interferes with a signal emanating from the T-cell receptor complex that induces IL-2 gene transcription.
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PMID:Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA. 205 9

Anti-Tac(Fv)-PE40 is a recombinant single-chain immunotoxin containing the heavy and light variable regions of the anti-Tac monoclonal antibody fused to a mutant form of Pseudomonas exotoxin (PE). Anti-Tac binds to the p55 subunit of the human interleukin 2 (IL-2) receptor, and anti-Tac(Fv)-PE40 kills human or monkey cell lines that contain either the intact IL-2 receptor or its p55 subunit alone. To assess the usefulness of anti-Tac(Fv)-PE40 in treatment of IL-2 receptor-positive leukemia, we tested peripheral blood mononuclear cells from six patients with adult T-cell leukemia. In each of the six patients, anti-Tac(Fv)-PE40 was extremely cytotoxic to the malignant cells. Metabolic activity and sensitivity of the fresh cells improved when a small amount of IL-2 (10 units per ml) was present during incubation. The toxin concentration necessary to inhibit protein synthesis by 50% after 16-hr incubation of cells with immunotoxin varied from 1.6 to 16 ng/ml (2.5-25 x 10(-11) M). In every case, binding was by means of the Tac antigen because anti-Tac(Fv)-PE40 cytotoxicity was prevented by adding excess anti-Tac antibody. Moreover, anti-Tac alone or an inactive mutant of anti-Tac(Fv)-PE40 without ADP-ribosylation activity had very little cytotoxic activity. Peripheral blood mononuclear cells from normal controls, from a patient with Tac-negative leukemia, and from adult T-cell leukemia patients without significant peripheral blood involvement were not sensitive to anti-Tac(Fv)-PE40. These results indicate that anti-Tac(Fv)-PE40 is a potent cytotoxin against adult T-cell leukemia cells in vitro and warrants clinical testing.
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PMID:The recombinant immunotoxin anti-Tac(Fv)-Pseudomonas exotoxin 40 is cytotoxic toward peripheral blood malignant cells from patients with adult T-cell leukemia. 223 41

Murine splenocytes immune to influenza virus-activated human T-cells were fused with SP2/0 cells, selected in chemically defined HAT media, and subcloned to yield a monoclonal antibody (MAb) termed 7G7/B6. 7G7/B6 binds to lectin- and antigen-activated T-cells, but not resting T-cells or B-lymphoblastoid lines from the same donor. 7G7/B6 immunoprecipitates a 50-55 kD band from cell surface iodinated PHA-activated T-cells or the T-cell leukemia line HUT 102B2, as shown on SDS-PAGE. Cross-clearing studies demonstrate that 7G7/B6 binds the same cell surface molecule(s) as anti-Tac, a MAb which has been shown previously to recognize the human receptor for IL-2. 35S-methionine pulse chase experiments in HUT 102B2 cells reveal that 7G7/B6 binds to an early (less than 30 min) 35-37 kD and late (greater than 4 h) 50 kD protein. Sequential immunoprecipitations demonstrate that these are identical to the molecules identified by anti-Tac under similar conditions. However, only anti-Tac coprecipitates a higher molecular band at 110 kD. 7G7/B6 and anti-Tac do not competitively inhibit the binding of each other to PHA-activated T-cells. Functional studies reveal that in contrast to anti-Tac, 7G7/B6 has almost no inhibitory effect in vitro on IL-2-driven proliferation of IL-2-dependent T-cell lines, or alloimmune cytotoxic T-cell generation (however, once generated, these cytotoxic T-cells were both 7G7/B6 and anti-Tac positive). Finally, IL-2 does not inhibit the binding of 7G7/B6 to activated T-cells under conditions which result in up to 75% inhibition of anti-Tac binding. Therefore, 7G7/B6 is another MAb recognizing the human IL-2 receptor, but binding to an epitope distinct from that recognized by either IL-2 or anti-Tac.
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PMID:A monoclonal antibody 7G7/B6, binds to an epitope on the human interleukin-2 (IL-2) receptor that is distinct from that recognized by IL-2 or anti-Tac. 240 92

IL-2-PE40 is a chimeric protein composed of human interleukin 2 (IL-2) genetically fused to the amino terminus of a modified form of Pseudomonas exotoxin lacking its cell recognition domain. IL-2-PE40, which is extremely cytotoxic to IL-2 receptor-positive cells, was examined for its ability to prevent graft rejection in mice in which activation of T cells is prominent. We demonstrate that intraperitoneally administered IL-2-PE40 specifically and significantly prolongs the survival of vascularized heart allografts in mice. The chimeric toxin, IL-2-PE40, offers an alternative approach to the treatment of autoimmune diseases and transplant rejection in humans.
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PMID:Cardiac allograft survival in mice treated with IL-2-PE40. 264 40

cDNAs for human interleukin-2 receptor were recently cloned and sequenced (Leonard et al., 1984, Nature 311, 626-631; Nikaido et al., 1984, Nature 311, 631-635; Cosman et al., Nature 312, 768-771). In the studies reported here, we describe the expression of a cDNA clone for the human interleukin-2 receptor in E. coli using an "open reading frame" expression vector pMR100. The inserted cDNA was expressed in E. coli transformants as a tripartite fusion polypeptide fused to the lambda cI protein at its amino terminus and to beta-galactosidase at its carboxy terminus. We demonstrate that the bacterially produced IL-2 receptor protein can bind to IL-2.
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PMID:Expression of human interleukin-2 receptor cDNA in E. coli. 302 92

The cellular receptors for interleukin 2 (IL-2) exist in at least two forms, one with a particularly high affinity and a second, more numerous class, with a much lower affinity for IL-2. Indirect evidence suggests that both classes of receptors use the same p55 glycoprotein as their ligand-binding component. L cells transfected with cDNA encoding this protein, however, displayed only low-affinity IL-2 binding. To determine if such receptors could be converted to a high-affinity state, L-cell membranes containing the murine p55 protein were fused with membranes from human T cells displaying high-affinity receptors. The anti-Tac antibody was used to block ligand binding to human p55 on the fusion product. The results showed that a fraction of the murine p55 chains were converted to a dramatically higher affinity following fusion. Fusion of the L-cell membranes with themselves or with membrane preparations from human T-cell lines lacking the IL-2 receptor resulted in little or no affinity modulation. One explanation of the results is that cofactors present in receptor-positive T-cell lines crossed species lines and combined with the murine p55 chain to create "high-affinity" binding sites. Thus, depending upon its environment, the same p55 molecule can apparently form either a low- or high-affinity IL-2 receptor.
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PMID:Conversion of low-affinity interleukin 2 receptors to a high-affinity state following fusion of cell membranes. 308 75

A cDNA clone for human interleukin 2 (IL-2) has been fused to the 5' end of a modified Pseudomonas exotoxin (PE) gene that lacks the sequences encoding the cell recognition domain. The chimeric protein IL-2-PE40 was produced in Escherichia coli. It was extremely toxic to IL-2 receptor-positive cells but had no measurable effect on cells lacking the IL-2 receptor. IL-2-PE40 might be a useful cytotoxic agent in the treatment of diseases involving IL-2 receptor-positive cells and in the treatment of allograft rejection.
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PMID:Cytotoxic activity of an interleukin 2-Pseudomonas exotoxin chimeric protein produced in Escherichia coli. 312 99

Human lymphocytes stimulated with phytohaemagglutinin (PHA) were fused with an HGPRT- murine lymphoma, BW5147, and a hybridoma BwFc93-1 was isolated and cloned in agarose. This human X mouse hybrid and nine clones derived from it were characterized by chromosome analysis, phenotypic and functional assays. Karyotyping and isoenzyme studies showed the presence of five human chromosomes in BwFc93-1 with preferential retention of three chromosomes--6, X and 15--in the clones. Membrane immunofluorescence analysis revealed that all the clones expressed human and mouse class 1 MHC antigens and the mouse T cell antigens Thy-1 and T200, but were devoid of human OKT3, OKT8 and mouse Lyt-2. Human OKT4 and OKM1 phenotypes were transiently expressed by one clone and mouse Lyt 1 by two other clones. Several T4-, Lyt-1- clones produced and bound human interleukin-2 (IL-2) indicating a lack of correlation between human T cell phenotype and function in those hybrids. There was also evidence of dichotomy in the secretion of IL-2 and expression of the IL-2 receptor since clones were identified which either bound or secreted IL-2. One clone expressing IL-2 receptors could be induced to produce human IL-2 by simultaneously stimulating with PHA and phorbol myristate acetate (PMA).
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PMID:Characterization of a human X mouse T cell hybridoma and identification of a clone secreting and binding interleukin-2. 660 21


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