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)

It has previously been described that V gamma 3 cells can proliferate extensively in vitro in the presence of different cytokines. Here, the role of cytokines in the maintenance of V gamma 3 cells in the thymus has been determined. Culture of fetal thymocytes in cell suspension for 24 h showed that, whereas immature TCRlowHSAhigh V gamma 3 cells remained viable, all mature TCRhighHSAlow V gamma 3 cells died. These cells died by apoptosis since protein synthesis was required and flow cytometric analysis as well as DNA gel electrophoresis showed that the DNA was degraded to oligonucleosomal bands. Addition of IL-2, IL-4 or IL-7 to suspension cultures of fetal thymocytes rescued V gamma 3 cells from dying. Addition of IL-1, IL-3, IL-5, IL-6, IL-9, TNF-alpha or IFN-gamma was without effect. Phenotypic analysis showed that the alpha-chain of the IL-2 receptor (IL-2R alpha) was expressed by part of the immature V gamma 3 thymocytes, all mature V gamma 3 cells expressed the beta-chain of the IL-2 receptor (IL-2R beta). Addition of anti-IL-2R beta mAb to fetal thymic organ culture (FTOC) resulted in a moderate reduction of the cell number of mature V gamma 3 thymocytes. Addition of anti-IL-2R alpha, anti-IL-4 or anti-IL-7 mAb had no effect. The cell number of mature V gamma 3 cells was highly reduced when both anti-IL-2R beta and anti-IL-7 mAb were added to FTOC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine dependence of V gamma 3 thymocytes: mature but not immature V gamma 3 cells require endogenous IL-2 and IL-7 to survive--evidence for cytokine redundancy. 754 10

A protein-tyrosine phosphatase LC-PTP is preferentially expressed in hematopoietic cells and is an early response gene in lymphokine stimulated cells. Here, we found the LC-PTP mRNA induction by IL-2 was markedly inhibited by several tyrosine kinase inhibitors. The induction required both the acidic and serine-rich regions of the IL-2 receptor beta chain (IL-2R beta) in mouse IL-3-dependent pro-B BAF-B03 transfectants. This is strikingly different from the induction of c-myc gene expression, which requires the serine-rich region alone. In addition, overexpression of activated-Lck or -Raf kinases resulted in augmented LC-PTP mRNA expression in myeloid cell line 32D transfectants. Considering the previous findings that the acidic region of the IL-2R beta is responsible for association with Lck and activation of Raf kinase, IL-2-induced expression of LC-PTP mRNA may be primarily transduced through a Lck-Raf mediated signaling pathway.
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PMID:IL-2-induced gene expression of protein-tyrosine phosphatase LC-PTP requires acidic and serine-rich regions within IL-2 receptor beta chain. 755 30

We have previously identified a critical region for growth signal transduction in the cytoplasmic domain of the human IL-4 receptor (hIL-4R). Since the entire cytoplasmic domain of this receptor lacks known catalytic activities such as the tyrosine kinase domain, it is likely that the IL-4R associates with other signal-transducing molecules through this critical cytoplasmic region. We test here whether a synthetic peptide corresponding to this critical cytoplasmic region, designated SP-1, interferes with IL-4-induced proliferation by competing with the IL-4R for binding to intracellular signal-transducing molecules. Our data indicated that 100 micrograms/ml SP-1 peptide completely inhibits human IL-4 (hIL-4)-induced proliferation of Ba/F3 transfectants expressing the full-length hIL-4R (hIL-4R-Ba/F3 transfectants). In contrast, a wide concentration range of an unrelated synthetic peptide, designated SP-2, did not affect hIL-4-induced proliferation of hIL-4R-Ba/F3 transfectants. This difference between SP-1 and SP-2 peptides was not due to their differential uptake by cell, since approximately 100 times more SP-2 peptide could be found in cytoplasmic extracts than SP-1 peptide in experiments using radiolabeled peptides. The specificity of SP-1-mediated inhibition of IL-4-induced proliferation was supported by the fact that the SP-1 peptide had no effect on IL-3-induced proliferation of the same hIL-4-Ba/F3 transfectants. In addition, the SP-1 peptide did not affect either IL-2-induced proliferation of Ba/F3 transfectants expressing the human IL-2 receptor beta chain (hIL-2R beta) or hIL-4-induced proliferation of Ba/F3 transfectants expressing a chimeric receptor consisting of the hIL-4R extracellular domain and the hIL-2R beta cytoplasmic domain. SP-1 was unable to inhibit IL-4-induced proliferation of other IL-4-responsive cell lines such as human erythroleukemic cell line TF-1 and mouse T cell lines HT2 and CTLL-2. In addition, SP-1 caused only a 50% inhibition of Ba/F3 cell proliferation induced by mouse IL-4. The failure of SP-1 to inhibit IL-4-induced proliferation in these various cell lines while producing excellent inhibition of hIL-4-induced proliferation of hIL-4R-Ba/F3 transfectants appeared to be related to the number of IL-4Rs expressed on each cell type.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A synthetic peptide corresponding to a critical intracellular signaling region of the human IL-4 receptor inhibits IL-4-induced proliferation. 760 96

The intravenous injection of mice with lymphocytic choriomeningitis virus (LCMV) induces a rapid and long-lasting immunodeficiency. T lymphocytes from 7-day-infected mice do not proliferate in vitro in response to ConA stimulation, do not produce IL-2 but display high affinity IL-2 receptors on their membrane. The non-coordinated regulation of these genes suggested that other cytokine-encoding genes may also be affected in their regulation. We have thus analyzed the expression of the genes encoding different cytokines transcribed during spleen cell activation by ConA. The genes encoding T lymphocyte-derived cytokines can be classified in three groups: the genes expressed similarly by normal and LCMV-cells (the p55 and the p75 chains of the IL-2 receptor [1]), the genes under expressed in LCMV-cells (IL-2, IL-3, IL-4 and IL-5) and the genes over expressed by these cells (GM-CSF and IFN-gamma). These results show that the viral infection has provoked a profound alteration of the overall regulation of the genetic program that follows T lymphocyte activation. Since T cell activation depends strictly on accessory cell-derived cytokines, we measured the level of transcription of IL-1, IL-6 and TNF-alpha; and our data show that the expression of these genes is equivalent in normal cells and in cells from LCMV-infected mice.
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PMID:Altered cytokine genes expression by conA-activated spleen cells from mice infected by lymphocytic choriomeningitis virus. 768 35

Growth factors have been defined by their ability to promote the proliferative expansion of receptor-bearing cells. For example, antigen-activated T cells expressing the alpha beta gamma form of the interleukin 2 (IL-2) receptor will proliferate in response to IL-2. In contrast, resting T cells, which express the IL-2 receptor beta and gamma chains, do not proliferate in response to IL-2. We demonstrate that the survival of resting T cells following gamma irradiation is greatly enhanced by pretreatment with IL-2. The radioprotective effect of IL-2 is dose dependent, does not result from the induction of cell proliferation, and does not require expression of the IL-2 receptor alpha chain. Thus, the beta gamma IL-2 receptor expressed on resting T cells can transduce signals that promote cell survival without committing the T cell to undergo cell division. IL-4 and IL-7, but not IL-1, IL-3, or IL-6, were also found to enhance the survival of quiescent T cells following gamma irradiation. Thus, certain growth factor-receptor interactions can serve to maintain cell viability in a manner that is independent of their ability to initiate or maintain cell proliferation. These data may have important implications for the use of growth factors in patients being treated with radiation and/or chemotherapy.
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PMID:Growth factors can enhance lymphocyte survival without committing the cell to undergo cell division. 777 36

The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (AS101) has previously been found by us to have radioprotective properties when injected into mice before sublethal and lethal doses of irradiation. AS101 also was found to protect mice from hematopoietic damage caused by various chemotherapeutic drugs. Based on these findings, phase II clinical trials with cancer patients treated with AS101, in combination with chemotherapy, are currently underway. In the present study, we wanted to assess the role of several cytokines in the radioprotection conferred by AS101. We show that the administration of neutralizing antibodies against interleukin-1 (IL-1) receptor, IL-6 receptor, IL-6, tumor necrosis factor (TNF), or stem cell factor (SCF) completely abrogates the ability of AS101 to increase the survival of lethally irradiated mice. Moreover, the injection of each of these antibodies reduces the ability of AS101 to increase the number of BM, spleen cells, and the number of circulating neutrophils, lymphocytes, and platelets in irradiated mice. In addition, these antibodies abrogate the enhancing effect of AS101 on the secretion of IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor, all of which decrease significantly in sublethally irradiated mice. By contrast, the injection of anti-IL-2 receptor antibody or control Igs to AS101-treated mice does not interfere with the radioprotective effects of the compound. These results suggest a role for IL-1, IL-6, TNF alpha, and SCF in the radioprotective effect of AS101. Because cytokine toxicity remains a significant concern, the clinical application of AS101, which has no toxicity, is particularly valuable.
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PMID:Role of endogenous cytokines secretion in radioprotection conferred by the immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate. 788 74

IL-2 regulates growth and differentiation of various types of cells in the immune system via its interaction with IL-2 receptor (IL-2R). The high and intermediate-affinity IL-2Rs, which consist of the alpha beta gamma heterotrimer complex and the beta gamma heterodimer complex, respectively, harbor the function of the intracellular signal transduction, indicating that the beta and gamma chains are indispensable for the signal transduction but not the alpha chain. The reconstitution studies of IL-2Rs with alpha, beta and gamma chain genes demonstrated that each subunit has potential for altering the affinity of the receptor, and the cytoplasmic domains of the beta and gamma chains participate in signal transduction in terms of cell growth, activation of alpha tyrosine kinase and enhancement of c-myc, c-fos and c-jun transcription. The region containing the SH2 homologous sequence of the gamma chain should have a critical function for signal transduction. On the other hand, common subunits are known to be shared among receptors for IL-3, IL-5 and GM-CSF, and receptors for IL-6, LIF, OSM and LIF. We have demonstrated that the monoclonal antibody specific for the IL-2R gamma chain completely inhibited not only IL-2-dependent cell growth but also IL-4-dependent, IL-7-dependent, and IL-9-dependent cell growth, suggesting that the gamma chain is possibly shared among receptors for IL-2, IL-4, IL-7 and IL-9. Impairment of the gamma chain function is considered to be closely related to human XSCID characterized by profound T cell defect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Structure and function of IL-2 receptor subunits]. 802 15

We have recently shown that a single transfusion of red blood cells to normal human volunteers significantly increases the secretion of a variety of cytokines. In the present study we explored the in vitro effect of whole red blood cells on various T cell and monocytes functions of autologous human or mouse origin. This in vitro model would allow us to further determine in future studies the membranal determinants or the intracellular products of the RBC responsible for the enhancing effect. We demonstrate in this study that addition of autologous erythrocytes to human mononuclear cells or mouse spleen cell cultures results in enhancement of cellular responses to suboptimal concentrations of mitogens. These include cell proliferation, the secretion of IL-2, colony stimulating factor (CSF), interferon-gamma, tumor necrosis factor, and interleukin-6 by human MNC, and cell proliferation, IL-2, IL-3, and CSF by mouse spleen cells. The enhancing effect was dose dependent. Moreover, RBC are shown to directly enhance the expression of IL-2 receptors on both human and mouse cells without the need for the presence of mitogenic stimulation. The expression of IL-2R was measured both by acquisition of responsiveness to exogenous recombinant IL-2 and by immunofluorescence staining. We suggest that whole red blood cells exert a general enhancing effect on the secretion of a variety of cytokines and induce IL-2 receptor expression, probably through nonspecific interaction between membranal domains on erythrocytes and CD2 antigen on T cells.
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PMID:Enhancing effects of autologous erythrocytes on human or mouse cytokine secretion and IL-2R expression. 809 64

Although parathyroid hormone-related peptide (PTHRP) is produced by adult T cell leukemia (ATL) cells and causes hypercalcemia in ATL patients, very little is known about the regulation of PTHRP gene expression in the leukemic cells. The present study was undertaken to clarify the role of T cell growth factor, interleukin-2 (IL-2), in the expression of PTHRP gene, using a human T cell leukemia virus type I (HTLV-I)-infected T cell line, MT-2. Recombinant human IL-2 caused a transient increase in the steady state level of PTHRP messenger RNA (mRNA) in MT-2 cells, and a maximal effect was observed at 3-6 h. The effect of IL-2 was dose dependent, with a maximal response being observed at 10(-10) M. A monoclonal antibody against IL-2 receptor (anti-Tac antibody) inhibited the IL-2-induced increase in PTHRP mRNA level. Recombinant human IL-1, IL-3, IL-4, and IL-6 failed to increase PTHRP mRNA level. Nuclear run-off transcription assay showed that the transcription rate of the PTHRP gene was modestly increased by IL-2. In addition, IL-2 caused a substantial increase in the stability of PTHRP mRNA, compared with control cells in which the apparent half-life of PTHRP mRNA was less than 30 min after RNA synthesis was inhibited by the RNA polymerase II inhibitor, dichlorobenzimidazole riboside. The secretion of PTHRP, as determined by both a newly established immunoradiometric assay using recombinant human PTHRP(1-87) as the standard and an RIA using an antibody against PTHRP(109-141), was increased by IL-2 but not by IL-1, IL-3, IL-4, or IL-6. The IL-2-induced increase in PTHRP secretion was completely inhibited by the addition of anti-Tac antibody. These results demonstrate that IL-2 stimulates the production and secretion of PTHRP by HTLV-I-infected T cells through specific binding to IL-2 receptor and that the effect of IL-2 is mediated by a posttranscriptional as well as a transcriptional mechanism. It is suggested that IL-2 may be involved in an auctocrine/paracrine fashion not only in the proliferation of HTLV-I-infected T cells but also in the enhanced production and secretion of PTHRP and thus the development of hypercalcemia in ATL patients.
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PMID:Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia. 809 24

The present study investigates the effect of transforming growth factor (TGF)-beta on the production of IL-4 and IFN-gamma by the leukemia Th0 type cell line HUT78, by freshly isolated human T cells, and by antigen specific human T cell clones. We found that IL-4 and IFN-gamma, but not IL-2, production by stimulated HUT78 cells was inhibited by TGF-beta 1. TGF-beta 1 also reduced the accumulation of IL-4 and IFN-gamma specific mRNA in stimulated HUT78 cells. However, IL-2 and IL-7 co-stimulated IL-4 and IFN-gamma production, whereas IL-1, IL-3, IL-5, IL-6, IL-8, tumor necrosis factor-alpha or granulocyte macrophage colony stimulating factor had no effect. Because IL-2 is an important helper cytokine for the production of IL-4 and IFN-gamma, we investigated whether signal transduction through the IL-2 receptor is impaired by TGF-beta 1. We found that tyrosine phosphorylation in response to IL-2 in HUT78 cells was strongly inhibited by a short preincubation with TGF-beta 1. Evidence for an antagonistic role for TGF-beta 1 and IL-2 comes from the finding that high doses of IL-2 could partially overcome TGF-beta 1 mediated inhibition of IL-4 and IFN-gamma production. Similar to its effect on HUT78 cells, TGF-beta 1 also inhibited IL-4 and IFN-gamma production by freshly isolated T cells as well as by human T cell clones. Taken together, our experiments show that the IL-2 dependent cytokines IL-4 and IFN-gamma are both negatively controlled by TGF-beta under conditions where IL-2 production is unaffected by a mechanism which partially involves an inhibition of IL-2/IL-2R signal transduction. These data identify TGF-beta and IL-2 as mutual antagonists in the regulation of IL-4 and IFN-gamma production.
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PMID:Transforming growth factor-beta inhibits IL-4 and IFN-gamma production by stimulated human T cells. 818 98


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