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)

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

Mast cells (MCs) originate from multipotent hematopoietic progenitor cells. However, MCs in various organs are heterogenous in terms of mediator or receptor expression and response to diverse stimuli. We characterized the phenotype and functional properties of human renal mast cells (HRMCs). Tissue was obtained from 17 patients suffering from renal tumors (transitional cell carcinoma, n = 4; renal cell carcinoma, n = 13). HRMCs were isolated by collagenase digestion. Double staining with toluidine blue and immunofluorescence using monoclonal antibodies (mAbs) revealed expression of stem cell factor (SCF)-receptor (c-kit/CD117), CD9, CD29, CD33, CD43, CD44, CD54, and CD63 on HRMCs. In contrast, HRMCs were not recognized by mAbs to CD2, CD3, CD4, CD11b, CD14, CD15, CD16, CDw17, CD19, or CD23. HRMCs were also negative for CD116 (granulocyte-macrophage colony-stimulating factor [GM-CSF] receptor alpha), CD123 (interleukin [IL]-3Ralpha), CD121a (IL-1R type I), CD122 (IL-2Rbeta), and CD127 (IL-7R) and were also found to lack C5aR (CD88). Ligand-induced activation of HRMCs through immunoglobulin (Ig)E-R or SCF-R (c-kit) resulted in histamine secretion (control: <10%; alphaIgE, 1 microg/mL: 50.12 +/-5.18%; rhSCF, 100 ng/mL: 29.24 +/- 22.39), whereas recombinant C5a, erythropoietin (EPO), IL-1 through 10, and GM-CSF exerted no effects. As determined by in situ staining, HRMCs contained tryptase, but only low or undetectable amounts of chymase. Electron microscopy confirmed the presence of MCs in renal tissues and revealed a scroll-rich granule population in HRMCs. Together, HRMCs are tryptase+, C5aR- mast cells exhibiting phenotypic and functional properties similar to those of lung MCs.
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PMID:Phenotypic and functional characterization of mast cells derived from renal tumor tissues. 947 5

Antibody to pneumococcal surface protein A (PspA) has been shown to be protective for Streptococcus pneumoniae infections in mice. In an attempt to define a model for inducing protective antibody to PspA in the absence of adjuvant, we designed two genetic fusions, PspA-interleukin-2 [IL-2]) and PspA-granulocyte-macrophage colony-stimulating factor (GM-CSF). These constructs maintained high cytokine function in vitro, as tested by their activity on IL-2 or GM-CSF-dependent cell lines. While intranasal immunization with PspA induced no detectable anti-PspA response, both PspA-IL-2 and PspA-GM-CSF stimulated high immunoglobulin G1 (IgG1) antibody responses. Interestingly, only the PspA-IL-2, not the PspA-GM-CSF, construct stimulated IgG2a antibody responses, suggesting that this construct directed the response along a TH1-dependent pathway. Comparable enhancement of the anti-PspA response with similar isotype profiles was observed after subcutaneous immunization as well. The enhancement observed with PspA-IL-2 was dependent on IL-2 activity in that it was not seen in IL-2 receptor knockout mice, while PspA in alum induced high-titer antibody in these mice. The antibody was tested for its protective activity in a mouse lethality model using S. pneumoniae WU-R2. Passive transfer of 1:90 dilutions of sera from mice immunized with PspA-IL-2 and PspA-GM-CSF elicited protection of CBA/N mice against intravenous challenge with over 170 50% lethal doses of capsular type 3 strain WU2. Only 0.17 microg or less of IgG antibody to PspA was able to provide passive protection against otherwise fatal challenge with S. pneumoniae. The data demonstrate that designing protein-cytokine fusions may be a useful approach for mucosal immunization and can induce high-titer systemic protective antibody responses.
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PMID:Enhanced protective antibody responses to PspA after intranasal or subcutaneous injections of PspA genetically fused to granulocyte-macrophage colony-stimulating factor or interleukin-2. 952 75

Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differentiation propagated from bone marrow or early thymic precursor cells with hematopoietic cytokines. In our study, we have induced growth and differentiation of DC from cord blood CD34+ cells initiated in interleukin-2 (IL-2) alone or in IL-2 + stem cell factor (SCF) + tumor necrosis factor alpha (TNF-alpha)-supplemented medium and cultured with IL-2 or IL-2 + SCF for 28-35 days. Dendritic morphology and antigenic phenotype of DC grown with IL-2 were characteristic for DC cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Growth and differentiation of DC was followed by an increase in expression of MHC II and co-stimulating molecules CD80 and CD86. We have also shown the expression of the IL-2 receptor (IL-2R) gamma-chain in CD34+ cells after 2-3 days of culture with IL-2 alone. The co-expression of the IL-2R alpha, beta, and gamma subunits in both DC cultured with IL-2- or GM-CSF-containing cocktail of cytokines was also shown. The time curve for induction of IL-2R demonstrated low levels of subunit expression at the beginning of culture. The number of CD1a cells co-expressing CD25, CD122, and CDgamma increased to about 24-68 and to 78-95% after 21 and 28-35 days, respectively. Development of natural killer cells was shown along with DC. The proportion of CD56+ cells and cytotoxicity increased in a time-dependent manner.
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PMID:Interleukin-2-induces development of denditric cells from cord blood CD34+ cells. 958 7

Multiple cytokines, including IL-2, can affect T cell proliferation and survival. However, IL-2 can lead to apoptosis as well as proliferation, making unclear whether IL-2 receptor (IL-2R) signals ultimately have a predominantly positive or negative effect. To address this issue, we examined the effect of enhancing IL-2R signals in CD8(+) T cells after antigen stimulation by engineering a transgenic (Tg) mouse strain with CD8(+) T cells capable of augmented, regulated, autocrine IL-2R signaling after target recognition by means of expression of a chimeric granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-2R. The Tg CD8(+) T cells can bind the granulocyte-macrophage colony-stimulating GM-CSF produced by antigen stimulation, but the GM-CSF binding results in delivery of an IL-2R signal. After antigen stimulation in vivo, the Tg T cells demonstrated marked increases in the initial proliferative response and cell expansion and displayed continued increases in cell expansion after repeated antigen exposure. These data suggest that the predominant role of IL-2R signals delivered to responding CD8(+) T cells is to set the size of the initial response to antigen by promoting T cell proliferation and survival and not cell death.
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PMID:Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. 1186 36

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1beta that was abrogated by a neutralizing antibody to the IL-4 receptor alpha (IL-4Ralpha)-chain but not to the IL-2 receptor gamma (IL-2Rgamma)-chain. Expression of cell surface IL-4 receptors and IL-4Ralpha in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1beta. Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1beta. However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1beta, was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1beta is mediated by a constitutive cell surface IL-4Ralpha and the activation of multiple intracellular pathways.
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PMID:Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. 1195 62

Cytokines may enhance the effect of therapeutic monoclonal antibodies (mAb). Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) have been shown to increase ADCC levels. GM-CSF may augment the induction of an idiotypic network response (anti-tumour immunity). The clinical anti-tumour effect of a combination of mouse mAb17-1A-1A [anti-colorectal carcinoma (CRC)], and GM-CSF was, however, not enhanced by the addition of IL-2. In the present study, some immune functions considered to be involved in mAb-mediated tumour cell killing were analysed in patients receiving GM-CSF and GM-CSF/IL-2 respectively together with the mAb17-1A-1A. Ten patients received mAb17-1A and GM-CSF, and ten patients mAb17-1A with GM-CSF and IL-2. During a 10- day cytokine treatment period, a significantly higher increase in white blood cell counts was noted in the GM-CSF/IL-2 treatment group as compared to GM-CSF-treated patients. In the GM-CSF/IL-2 group, significantly higher serum concentrations of neopterin and soluble IL-2 receptor (sIL-2R) respectively were induced as compared to GM-CSF-treated patients. However, the ADCC of peripheral blood mononuclear cells (PBMC) against a CRC cell line was significantly higher in the GM-CSF group than in the GM-CSF/IL-2 group. The frequencies of patients developing human anti-mouse antibodies (HAMA) and anti-idiotypic antibodies were the same in both groups, while serum concentrations were significantly lower in the GM-CSF/IL-2 group as compared to the GM-CSF group. GM-CSF/IL-2 therapy seems to induce an immune suppressive stage compared to GM-CSF alone affecting cytotoxic mononuclear cells and B cells, which might be mediated through the neopterin metabolic pathway or other inducible immune suppressive factors such as reactive oxygen and nitrogen intermediates.
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PMID:Treatment with GM-CSF and IL-2 in patients with metastatic colorectal carcinoma induced high serum levels of neopterin and sIL-2R, an indicator of immune suppression. 1207 Jul 12

Previous studies in cancer patients demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated the interleukin (IL)-2 receptor on T lymphocytes and monocytes suggesting that subsequently administered IL-2 would produce greater immune effects. The authors treated 21 patients with metastatic renal cell carcinoma and melanoma on a randomized phase I study to test this hypothesis. All 21 patients received a fixed dose of IL-2 (72,000 IU/kg every 8 hours for 5 days) administered intravenously as an inpatient. Patients were randomized to receive IL-2 alone or in combination with GM-CSF at a dose of 125 or 250 mcg/m /d (Sargramostim; Immunex Corporation, WA, U.S.A.) daily for 7 days by subcutaneous injection starting on day 1, the day before IL-2 treatment. The results from this study demonstrated that GM-CSF did not worsen the toxicities produced by IL-2 alone. Grade 3 confusion occurred in four patients, three who received IL-2 alone. No partial or complete tumor responses were seen. Assays of serum soluble IL-2 receptor (sIL2R) and neopterin, measures of T cell and monocyte activation, respectively, demonstrated a significant increase in sIL2R but not neopterin, 24 hours after the first dose of GM-CSF. In combination with IL-2, the higher dose of GM-CSF (250 mcg/m ) produced higher sIL2R levels on days 3 and 7 than the 125-mcg/m dose of GM-CSF or IL-2 alone. Although neopterin levels did not increase after 1 day of GM-CSF, the addition of IL-2 resulted in a significantly increased neopterin level on day 3 at the higher dose of GM-CSF. On day 7, neopterin levels in all three groups were similarly increased over baseline. Ten days after treatment, neopterin levels had returned to normal, but sIL2R levels remained markedly increased (12 fold) over baseline in the higher GM-CSF dose group. The authors conclude that 1) monocyte activation was not significantly enhanced by 1 day of GM-CSF treatment; 2) the 250-mcg/m GM-CSF dose plus IL-2 produced superior T cell activation compared with a lower dose of GM-CSF plus IL-2 or to IL-2 alone; and 3) the combination of GM-CSF and IL-2 was safe and tolerable but was not associated with any clinical responses.
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PMID:Immune effects of escalating doses of granulocyte-macrophage colony-stimulating factor added to a fixed, low-dose, inpatient interleukin-2 regimen: a randomized phase I trial in patients with metastatic melanoma and renal cell carcinoma. 1261

The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.
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PMID:Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. 1294 96

Recombinant interleukin-2 (IL-2) (aldesleukin, Proleukin, Chiron, Emeryville, CA) is approved for treatment of cancer patients and under investigation in HIV-infected individuals. However, treatment with aldesleukin is associated with toxicity, which may be due to its elicitation of inflammatory mediators from cells that express the intermediate-affinity IL-2 receptor. BAY 50-4798, a novel IL-2 analog, is a selective agonist for the high-affinity receptor. It induces the proliferation of activated T cells with a potency similar to that of aldesleukin but has reduced activity on cells expressing the intermediate-affinity receptor. In the current study, we compared cytokine responses elicited in peripheral blood mononuclear cell (PBMC) cultures stimulated with BAY 50-4798 or aldesleukin. BAY 50-4798 induced approximately 5-fold lower mean levels of endogenous IL-2 than aldesleukin, and at least 50% lower levels of proinflammatory cytokines, such as tumor necrosis fctor-alpha (TNF-alpha), IL-1beta, IL-6, and interferon-gamma (IFN-gamma). Furthermore, statistically significant reductions in the levels of IL-5, IL-8, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed in response to BAY 50-4798. These findings increase our understanding of the biologic action of BAY 50-4798 and suggest a mechanism by which it may exhibit better safety than aldesleukin in humans.
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PMID:Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. 1654 39

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