UNIPROT:P14784 - FACTA Search

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

The T cell antigen receptor (TCR) and the interleukin-2 receptor (IL-2R) are important receptors in haematopoiesis since they control the activation and growth of T lymphocytes, respectively. The term T cell activation refers to the events that occur as T cells progress from the G0 to the G1 phase of the cell cycle and is characterised by the production of a wide range of cytokines and other immunomodulators crucial for the growth and development of other haematopoietic cells. Activation also induces the T cells to express on their cell surface high affinity receptors for various cytokines which enable the T cell to respond to the different cytokines generated during an immune response. One well characterised event that occurs when mature T cells are activated is the production of the cytokine IL-2 and the acquisition by the T cell of high affinity IL-2 receptors. Interaction between IL-2 and its cellular receptor than direct T cell growth. One notable difference between TCR and IL-2R signal transduction is that the TCR regulates intracellular calcium and stimulates protein kinase C whereas the IL-2 receptor does not. The present review focuses on TCR and IL-2R regulation of two common intracellular signalling pathways: the regulation of a PtdIns-3-kinase and the activation of the guanine nucleotide binding proteins p21ras. The aim is to illustrate differences in the mechanisms that couple the TCR and IL-2R to these two signalling pathways and attempt to explain the apparent discrepancy of TCR and IL-2R regulation of shared signal transduction pathways even though these receptors mediate quite distinct biological responses.
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PMID:Regulation of PtdIns-3-kinase and the guanine nucleotide binding proteins p21ras during signal transduction by the T cell antigen receptor and the interleukin-2 receptor. 826 Jun 48

DAB486IL-2 is the first of a new class of targeted biologicals called fusion toxins. This agent is an interleukin-2 receptor (IL-2R)-targeted cytotoxin which kills activated IL-2R-expressing lymphocytes at 10(-10) M concentrations. Since activated lymphocytes are thought to play a role in many autoimmune conditions, DAB486IL-2 has been evaluated in patients with severe rheumatoid arthritis and recent onset autoimmune insulin-dependent diabetes mellitus. Initial safety, pharmacokinetics and evidence of IL-2R specific cytotoxicity were obtained in patients with IL-2 receptor expressing malignancies; these studies served as a basis for the initiation of an open label phase I/II evaluation of DAB486IL-2 in patients with severe, methotrexate refractory rheumatoid arthritis. This pilot study provided preliminary evidence of acceptable safety at doses which induced meaningful (> 25%) or substantial (> 50%) improvement in 9 of 18 patients who received a mid (130 kU/kg/d) or a high (260 kU/kg/d) dose daily for 5 to 7 days. The most frequent adverse effects were transient hepatic transminase elevation and fever. Although some patients noted a transient increase in joint pain, onset of improvement occurred within 7 to 14 days of initiation of DAB486IL-2. Because of these results, a two-center, double-blind, placebo-controlled trial was conducted from December 1991 to December 1992. Forty-five patients with active severe RA unresponsive to at least 2 DMARDS were randomized to placebo or DAB486IL-2 following a 3 to 4 week washout/run-in period to establish a stable baseline (< 40% fluctuation in swollen and painful, tender joint counts).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis and recent onset insulin-dependent diabetes mellitus. 832 45

The genes encoding the alpha- and beta-chains of the human interleukin-2 receptor were expressed in lepidopteran insect cells using the baculovirus expression vector system. The corresponding genes were inserted under the polyhedrin promoter of the Autographa california nuclear polyhedrosis virus and expressed in the Spodoptera frugiperda insect cell line during viral infection. The recombinant receptor proteins were identified in the insect cell lysates by using protein dot blot and ELISA techniques. At 36 h post infection the corresponding proteins were clearly detected using anti-IL-2 alpha- and beta-receptor-specific antibodies. A large amount of the alpha-chain was also found in the supernatant culture media at 72 h post infection and metabolic labelling with [35S]-methionine indicated that it was proteolytically cleaved into a 32 kDa soluble form. A similar soluble or secreted form of the beta-chain was, however, not observed. Both receptor proteins were expressed on the surface of the insect cells as determined by flow cytometry analysis. Studies performed with the different IL-2 receptor forms (alpha- and beta-chains alone or in combination) in the presence or absence of rIL-2 suggest that the receptor proteins when expressed in infected insect cells are non-functional with respect to tyrosine phosphorylation.
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PMID:Expression of human IL-2 receptor alpha- and beta-chains using the baculovirus expression system. 835 2

Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro with various stimuli and in the presence or absence of a 5-lipoxygenase (5-LO) inhibitor, A-63162, to measure its effects on PBMC proliferation, interleukin-2 receptor (IL-2R) expression, interleukin-2 (IL-2) synthesis, interleukin-6 (IL-6) synthesis, and accumulation of messenger RNA for IL-2 or IL-6. A-63162 inhibited PBMC proliferation stimulated by phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) plus A23187, IL-2 receptor expression stimulated by PHA, and IL-2 or IL-6 synthesis induced by PHA plus PMA or PMA plus A23187. At the same concentration, A-63162 inhibited accumulation of mRNA for IL-2 or IL-6 and also inhibited leukotriene B4 (LTB4) synthesis. Our data indicate that the 5-LO inhibitor A-63162 has immunosuppressive activity that may be due to inhibition of LTB4 production or to direct inhibitory actions of A-63162 on IL-2 and IL-6 synthesis.
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PMID:Inhibition of human mononuclear cell proliferation, interleukin synthesis, mRNA for IL-2, IL-6, and leukotriene B4 synthesis by a lipoxygenase inhibitor. 840 48

Cassette and deletion mutagenesis were used to analyze the function of the amphipathic alpha-helices in the transmembrane domain of DAB389-interleukin-2 (IL-2), a fusion protein which is targeted to the interleukin-2 receptor. We demonstrate that the in-frame deletion of 60 amino acids, from Asn204 to Glu263 in DAB389-IL-2, results in complete loss of cytotoxic activity, whereas when the amphipathic regions from Asp208 to Ser220 and Ala244 to His258 are replaced with idealized amphipathic helices composed of repeating Glu, Lys, and Leu residues, the mutant fusion toxin has low but detectable activity. DAB389-IL-2 and both variants form channels in artificial phospholipid bilayers with conductances identical to those formed by diphtheria toxin. Both mutant fusion toxins bind to the high affinity IL-2 receptor with affinities similar to that of DAB389-IL-2. The fact that these mutants have markedly reduced or absent cytotoxic activity, but possess "wild type" catalytic activity, binding affinities, and channel conductances, suggests the existence of a step in the intoxication pathway, defective in the mutants, which occurs after DAB389-IL-2 binds to the IL-2 receptor. It is unknown whether this step occurs prior or subsequent to channel formation, but it is essential for the efficient delivery of the ADP-ribosyltransferase from DAB389-IL-2 to the cytosol of target cells.
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PMID:Structure/function analysis of the transmembrane domain of DAB389-interleukin-2, an interleukin-2 receptor-targeted fusion toxin. The amphipathic helical region of the transmembrane domain is essential for the efficient delivery of the catalytic domain to the cytosol of target cells. 850 30

Some evidence points towards a possible autoimmune role in the aetiology of schizophrenia. Experimental findings provide contradictory results regarding abnormalities in cytokine production in this disorder. In the present study we tested the production of cytokines in CSF and serum in 16 schizophrenic patients and 10 healthy controls (tumor necrosis factor alpha - TNF alpha; interleukins IL-1 beta, IL-2, IL-6, soluble IL-2 receptor). Cytokine levels were evaluated by radioactively-labeled antibodies (IL-1 beta, IL-2, IL-6), by enzyme-linked immunoassay (TNF) and by a sandwich enzyme immunoassay (soluble IL-2 receptor). No significant differences were found in either CSF fluid or serum levels of TNF and IL-2 or IL-6. Interleukin-1 beta was significantly decreased in patients' CSF and serum as compared to controls. Soluble interleukin-2 receptor levels were decreased in CSF of patients, but highly increased in their serum in comparison with controls. Changes in various cytokine levels in CSF fluid and serum of schizophrenic patients probably reflect interrelated process of growth, degeneration or neuroimmunological abnormalities, which may all play a role in the pathophysiology of schizophrenia. The present study supports evidence for change in immune activation, probably of peripheral origin, in schizophrenic patients.
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PMID:Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. 856 79

A number of cytokines and growth factors use the JAK-STAT pathway to signal from the cell membrane to the nucleus. While homodimerizing cytokine receptors may transmit signal via a single form of JAK (i.e. growth hormone receptors), several multicomponent cytokine receptors have been shown to require simultaneous activation of pairs of different JAK kinases (i.e. interferon receptors). Recent evidence for a preferential coupling of JAK3 to interleukin-2 receptor-gamma (IL-2R gamma) and JAK1 to IL-2R beta supports the concept of heterotrans-activation of JAK1 and JAK3 caused by IL-2-induced heterodimerization of their receptor partners. The present study verified the ability of IL-2 to cause tyrosine phosphorylation and activation of JAK1 and JAK3, but demonstrated that IL-2 stimulated JAK3 to a significantly larger extent than JAK1 in human T lymphocytes and the YT cell line. This conclusion was based upon several independent criteria, including more vigorous tyrosine phosphorylation of JAK3, more marked enzymatic activation of JAK3 as well as higher abundance of JAK3 in activated IL-2 receptor complexes. Furthermore, when human IL-2R beta was stably expressed in murine BA/F3 cells, robust IL-2-induced proliferation and JAK3 activation occurred without detectable involvement of either JAK1, JAK2 or TYK2. We therefore propose that IL-2 receptor signal transduction does not depend on equimolar heterodimerization of JAK1 and JAK3 following IL-2-induced heterodimerization of IL-2R beta and IL-2R gamma. Nonetheless, a membrane-proximal region of human IL-2R beta (Asn240-Leu335) was critical for JAK3 activation, and the amount of JAK3 present in activated IL-2 receptor complexes increased with time, suggesting that stabilization of JAK3 binding to the receptor complex relies on both IL-2R beta and IL-2R gamma. Moreover, STAT5 was found to be the predominant STAT transcription factor used by IL-2 in human T cells, and specifically required a COOH-terminal region of IL-2R beta (Ser386-Val525), while STAT5 recruitment was not correlated to activation of IL-2R gamma or JAK3.
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PMID:Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain. 858 Mar 78

We analyzed primary-cultured human hepatic macrophages (HHMphi) from 12 patients with non-cirrhotic and cirrhotic livers for cell surface expression of HLA-DR antigen and interleukin-2 receptor (IL-2R). Compared to the relatively abundant HLA-DR antigen, IL-2R expression was generally low. No significant difference was observed between HLA-DR antigen expression nor IL-2 receptor expression. HHMphi from patients with serum hepatitis viral markers, however, expressed significantly more HLA-DR antigen than did HHMphi of patients without viral markers, which suggest a possible role of HHMphi as antigen-presenting cells (APC) in viral hepatitis. This direct, quantitative measurement of cell surface molecule expression on hepatic macrophages of human may provide an important clue to the pathophysiology of human liver disorders.
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PMID:HLA-DR antigen and interleukin-2 receptor expression on primary-cultured human hepatic macrophages in relation to liver cirrhosis and hepatitis virus infection. 863 8

Sixteen postnatal human thymuses were obtained at the time of corrective cardiovascular surgery and maintained in vitro as separate cultures of thymocytes and reticulo-epithelial (RE) cells. The stages of differentiation of the thymocytes were investigated in situ with a library of 10 monoclonal antibodies (MoABs) directed against human lymphocyte differentiation antigens. Employing immunofluorescence staining and flow cytometric (FACS) analysis, in vitro immunophenotype (IP) changes were demonstrated, which appeared after use of a combination of mitogen (PHA), recombinant interleukin-2 (rIL-2) and autologous thymic RE cell culture supernatants. RE cell supernatant participated in increasing the expression of the IL-2 receptor (IL-2R) during combined stimulation with phytohaemagglutinin (PHA) and rIL-2. Thymocyte proliferation was measured in 4 hour tritiated-thymidine (3H-TdR) incorporation (proliferation) assay. We were able to isolate the thymic nurse cells (TNC) with and without enzymatic tissue digestion. TNCs were separated from accompanying thymocytes and cultured. They grew as large, sometimes connected cells, but did not display the epithelial type of tissue organization. After in vitro culturing, the cytoskeleton of TNCs expressed high molecular weight cytokeratin and vimentin and intracytoplasmic tonofilaments, characteristic of epithelium. Whole thymic tissue pieces were cultured with and without previous trypsinization. The initial outgrowth of the cuboidal epithelial tissue layer occurred within 24-48 hours, and the RE cells remained functionally active for at least 15 days. RE cell supernatants were collected daily for two weeks and used in thymocyte differentiation experiments. The results indicated that thymic humoral factors contribute to a select, not fully understood differentiation pathway of thymocytes: a) more mature immunophenotype (IP) characterized by CD3 expression; b) de novo synthesis of interleukin-2 receptor (IL-2R); and; c) differentiation of the CD8+ subpopulation, identifying regulatory cells within the two major CD8+ and CD4+ subsets. Use of mitogenic (PHA) stimulation, after 5 days in vitro, resulted in a T helper (CD4+) oriented differentiation pathway of cortical thymocytes. At the same time, the cultured thymocytes expressed CD11 de novo, an early thymocyte differentiation antigen, and CD7, a marker not present on mature peripheral lymphocyte subsets (the IP changes demonstrated a dedifferentiation). Our overall impression, following the studies with the proliferation assays, was that in our experimental in vitro model, thymic hormones did not contribute to the induction of generalized thymocyte proliferation.
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PMID:Cell culture observations of human postnatal thymic epithelium: an in vitro model for growth and humoral influence on intrathymic T lymphocyte maturation. 889 32

As it has been suggested that an autocrine mechanism may control tumour cell growth, in this work cells from a spontaneous murine T lymphocyte leukaemia (LB) expressing the interleukin-2 receptor (IL-2R) (CD25) were evaluated in vitro for IL-2-mediated autocrine growth. Cells grew readily in culture and proliferation was enhanced by the addition of recombinant IL-2 but inhibited by monoclonal antibodies against either IL-2 or IL-2 receptor, in the absence of exogenous IL-2. Cyclosporin A also inhibited LB cell growth. However, when exogenous IL-2 was added together with cyclosporin A, cell proliferation proved similar to controls. Using reverse transcription polymerase chain reaction (PCR), mRNA for IL-2 was found to be present in tumour cells. Our findings support the hypothesis that LB tumour cell proliferation is mediated by an autocrine pathway involving endogenous IL-2 generation, despite the fact that these cells are not dependent on exogenous IL-2 to grow in culture.
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PMID:Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth. 908 28

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