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

Extracts of chorionic villous and decidual tissue specimens from women in the early stages of pregnancy contained stem cell factor (SCF), the amount in the latter tissue (246.6+/-119.7 pg/mg protein) being approximately three times that in the former. Immunohistochemical analysis revealed the presence of SCF in the mesenchymal cells of the chorion, the trophoblast, and decidual stromal cells, whereas the SCF receptor, c-kit, was detected in the trophoblast and decidual mononuclear leukocytes but not in decidual stromal cells. Reverse transcription and polymerase chain reaction analysis detected transcripts corresponding to both secretory and membrane-bound types of SCF in chorionic tissue, but only those encoding the secretory type in decidual tissue. Flow cytometric analysis showed that c-kit was expressed on decidual CD16- CD56bright natural killer (NK) cells, CD14+ macrophages, and CD34+ hematopoietic progenitor cells, but not on CD3+ T cells or CD16+ NK cells. Although SCF alone had no effect on DNA synthesis in decidual CD16- CD56bright NK cells, it enhanced the proliferative effect of interleukin-2 (IL-2) at IL-2 concentrations that selectively saturate the high-affinity IL-2 receptor (IL-2R). Flow cytometry of decidual mononuclear leukocytes cultured in the presence of SCF demonstrated that this factor increased the expression of the IL-2Ralpha chain, but not IL-2Rbeta and gamma chain expression on CD16- CD56bright NK cells. Results suggest that SCF produced in the decidua increases the expression of the IL-2Ralpha which is usually present in smaller amounts than other two IL-2R chains on decidual CD16- CD56bright NK cells, and thereby promotes the proliferation of these cells in response to low concentrations of IL-2, resulting in an increase of the high affinity IL-2Rs.
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PMID:Enhancement by stem cell factor of interleukin-2 (IL-2)-induced DNA synthesis in human decidual CD16- CD56bright natural killer cells mediated by increased expression of the IL-2 receptor alpha chain. 986 54

The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)-dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2 (PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56(lck), and p59(fyn)) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (gammac) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2-dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2-dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.
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PMID:Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. 1009 Sep 41

The resolution of immune responses is characterized by extensive apoptosis of activated T cells. However, to generate and maintain immunological memory, some antigen-specific T cells must survive and revert to a resting G0/G1 state. Cytokines that bind to the common gamma chain of the IL-2 receptor promote the survival of T cell blasts, but also induce proliferation. In contrast, soluble factors secreted by stromal cells induce Tcell survival in a resting G0/G1 state. We now report that interferon-beta is the principal mediator of stromal cell-mediated Tcell rescue from apoptosis. Interferon-alpha and -beta promote the reversion of blast Tcells to a resting G0/G1 configuration with all the characteristic features of stromal cell rescue; such as high Bcl-XL expression and low Bcl-2. Type I interferons and stromal cells stimulate apparently identical signaling pathways, leading to STAT-1 activation. We also show that this mechanism may play a fundamental role in the persistence of T cells at sites of chronic inflammation; suggesting that chronic inflammation is an aberrant consequence of immunological memory.
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PMID:Interferon-beta mediates stromal cell rescue of T cells from apoptosis. 1009 9

CD40 signaling induces B cell proliferative and differentiation responses that can be modulated by many different cytokines. Cytokines in the IL-2 receptor gamma chain (gammac)-common family are known to play an integral role in B cell development. Therefore, we investigated the possibility that CD40 signaling induced B cell responsiveness to multiple gammac-common cytokines and that individual gammac-common cytokines induced distinct B cell responses. B cells were isolated from lymphoid follicles of sheep Peyer's patches (PP) and co-cultured with murine CD40 ligand (mCD40L). CD40 signaling induced PP B cell responsiveness to recombinant human IL-2, IL-4, IL-7 and IL-15. mCD40L-induced B cell growth was enhanced by combining IL-4 with a second gammac-common cytokine and sustained B cell growth required co-stimulation with IL-4 plus IL-2, IL-7 and IL-15. gammac-common cytokine responsiveness remained dependent upon CD40 signaling, and removal of mCD40L resulted in B cell differentiation and cell death. Similar proliferative responses to mCD40L and gammac-common cytokines were observed for both immature (ileal) and mature (jejunal) PP B cells. Finally, the capacity of CD40-activated B cells to respond to multiple gammac-common cytokines was analyzed with individual PP B cell clones. All B cell clones displayed similar proliferative responses to IL-2 but quantitatively different responses to IL-4, IL-7 and IL-15. The biological significance of B cell responsiveness to multiple gammac-common cytokines is discussed.
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PMID:CD40 signaling induces B cell responsiveness to multiple members of the gamma chain-common cytokine family. 1038 47

Interleukin-13 (IL-13) is a pleiotropic cytokine that controls growth, differentiation, and apoptosis of immune and tumor cells. To understand the mechanisms of interaction between IL-13 and IL-13 receptors (IL-13R), and the role of the IL-2 receptor common gamma chain (gammac) in IL-13 binding and processing, we have examined IL-13 binding kinetics, dissociation/shedding, and internalization in renal cell carcinoma (RCC) cell lines. We observed a new phenomena in that the apparent rate of association, but not the dissociation, was strongly related to IL-13 concentration. We also observed cooperativity phenomena in IL-13 and IL-13R interaction in control RCC (MLneo) cells, but not in cells transfected with gammac chain (MLgammac). The number of IL-13 binding sites, the effective rate of ligand association, and the dissociation rate constants were reduced in gammac-transfected cells compared to control RCC cells. Two forms of IL-13R were detected in these cell lines, which differed in the kinetics of endocytosis and dissociation/exocytosis. Only a small fraction of bound receptors (14-24%) was rapidly internalized and the same fraction of the ligand-receptor complexes was shed and/or dissociated. The expression of gammac chain did not change any of these processes. A two independent high-affinity and moderate-affinity receptor model fit the kinetic observations in gammac-transfected cells. However, in control cells, the binding kinetics were more complicated. A mathematical model that fit a set of kinetic and steady state data in control cells was selected from a set of possible models. This best-fit model predicts that 1) two different IL-13R are expressed on the cell membrane, 2) a minor fraction of IL-13R exist as microclusters (homodimers and/or heterodimers) without exogenous IL-13, 3) high morphological complexity of the gammac-negative control cell membrane affects the cooperativity phenomena of IL-13 binding, and 4) a large number of co-receptor molecules is present, which helps keep the ligand on the cell surface for a long period of time after fast IL-13 binding and provides a negative control for ligand binding via production of the high affinity inhibitor bound to IL-13. Our data demonstrate that gammac exerts dramatic changes in the kinetic mechanisms of IL-13 binding.
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PMID:Kinetic analysis of high affinity forms of interleukin (IL)-13 receptors: suppression of IL-13 binding by IL-2 receptor gamma chain. 1038 47

The primary interleukin-4 (IL-4) receptor complex on monocytes (type I IL-4 receptor) includes the 140-kDa alpha chain (IL-4R alpha) and the IL-2 receptor gamma chain, gamma(c), which heterodimerize for intracellular signaling, resulting in suppression of lipopolysaccharide (LPS)-inducible inflammatory mediator production. The activity of IL-13 on human monocytes is very similar to that of IL-4 because the predominant signaling chain (IL-4R alpha) is common to both receptors. In fact, IL-4R alpha with IL-13R alpha1 is designated both as an IL-13 receptor and the type II IL-4 receptor. When the anti-inflammatory activities of IL-4 and IL-13 were investigated on synovial fluid macrophages and compared with the responses by monocytes isolated from the patients at the same time as joint drainage, the response profiles differed with some responses similar in the two cell populations, others reduced on the inflammatory cells. Similar differences were recorded in the response profiles to IL-4 and IL-13 by monocytes and monocytes cultured for 7 days in macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF) (monocyte-derived macrophages, MDMac). MDMac have reduced gamma(c) mRNA levels and reduced expression of the functional 64-kDa gamma(c). There was a similar loss of IL-13R alpha1 mRNA on monocyte differentiation. In turn, there was a significant reduction in the ability of IL-4 and IL-13 to activate STAT6. These findings suggest that different functional responses to IL-4 and IL-13 by human monocytes and macrophages may result from reduced expression of gamma(c) and IL-13R alpha1.
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PMID:Differential responses of human monocytes and macrophages to IL-4 and IL-13. 1053 11

Engagement of interleukin-2 (IL-2) mediates the heterodimeridation of the common beta chain (beta(c)) and common gamma chain (gamma(c)) of the IL-2 receptor (IL-2R). This is sufficient and necessary for receptor activation and signal transduction. It is generally held that the IL-2R is activated by the trans-activity of the protein tyrosine kinases (PTKs) Jak1 and Jak3 associated with beta(c) and gamma(c) respectively. Transduction of proliferative signals requires Jak3 activity. A Jak3 independent signalling pathway involving p56(lck), generating anti-apoptotic signals, can be observed and requires the PROX domain of gamma(c). p56(lck) can be activated by dephosphorylation of an inhibitory carboxyl terminal phosphorylated tyrosine residue (Y505). We propose that this is mediated by a PROX domain associated protein tyrosine phosphatase (PTP). Activation of p56(lck) alone is insufficient for transduction of proliferative signals and thus works in concert with Jak3 mediated receptor activation. This indicates that both gamma(c) domains are vital for signal transduction.
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PMID:Activation of the interleukin 2 receptor: a possible role for tyrosine phosphatases. 1088 65

Glucocorticoids (GCs) are potent anti-inflammatory agents that block cytokine production. We investigated whether GCs also block cytokine signaling via the Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway. Dexamethasone inhibited IL-2-induced DNA binding, tyrosine phosphorylation, and nuclear translocation of Stat5 in primary T cells. Inhibition of Stat5 correlated with inhibition of expression of IL-2-inducible genes and T cell proliferation. The mechanism of inhibition involved suppression of IL-2 receptor and Jak3 expression. Signaling by IL-4, IL-7, and IL-15, which use IL-2 receptor components, also was inhibited, indicating a block in T cell responses similar to that seen in immunodeficient patients lacking the IL-2 receptor gamma chain or Jak3. IL-2 signaling also was blocked in patients after treatment with GCs, suggesting that inhibition of cytokine signaling contributes to the clinical efficacy of these agents. These results identify inhibition of Jak-STAT signaling by IL-2 and related cytokines as a novel mechanism of GC action and suggest that inhibition of both cytokine production and signaling contribute to their therapeutic potency.
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PMID:Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids. 1092 Jan 90

Many of the actions and receptor components of interleukin-13 (IL-13), a pleiotrophic cytokine with immunotherapeutic potential, are shared with IL-4. Because human low-grade astrocytoma cells express IL-4 receptors and their growth is arrested by IL-4, we speculated that IL-13 sensitivity and receptor expression might also be present. The purpose of the current study was to investigate IL-13 receptor components and sensitivity in a series of glial cell lines derived from adult human non-neoplastic cerebral cortex, low-grade astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Unlike peripheral blood lymphocytes (PBL), glial cells did not express IL-2 receptor gamma chain. IL-13 receptor alpha-1 (IL-13Ralpha1), however, was present in 11/13 glial lines and PBL. Deficient cell lines were all glioblastoma-derived. All anaplastic astrocytoma and glioblastoma but not other glial lines or PBL expressed IL-13 receptor alpha-2 (IL-13Ralpha2). In non-neoplastic glia, low-grade, and anaplastic astrocytoma, IL-13 decreased DNA synthesis, an effect reversible with antibody to IL-4Ralpha. Results indicate that low-grade astrocytoma cells resemble non-neoplastic glia in terms of IL-13 sensitivity and IL-4Ralpha/IL-13Ralpha1 receptor profile but alterations occur with malignant progression. Glioblastoma cells were uniformly insensitive to IL-13 and, unlike other glia, failed to phosphorylate STAT6 after IL-13 challenge. Data suggest that IL-13 and analysis of IL-13 receptors may have clinical application in glial tumors.
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PMID:Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. 1094 14

X-linked severe combined immunodeficiency (XSCID) is caused by mutations in the IL-2 receptor gamma chain (IL2RG) gene, resulting in absent T lymphocytes and nonfunctional B lymphocytes. Recently T lymphocyte production and B lymphocyte function were restored in XSCID patients infused with autologous stem cells transduced with a retrovirus containing the human IL2RG cDNA. To optimize the expression of human IL2RG for future clinical trials, we compared five retroviral vectors expressing human IL2RG from different LTR enhancer-promoter elements in a mouse model. Northern and Southern blot analysis of hematopoietic tissues from repopulated mice revealed that the retroviral vector with the highest expression per copy number was MFG-S-hIL2RG, followed by MND-hIL2RG. All five vectors were capable of restoring lymphopoiesis in irradiated XSCID mice transplanted with transduced IL2RG-deficient hematopoietic stem cells. Transduction of IL2RG-deficient hematopoietic stem cells with all five vectors restored T lymphopoiesis in transplanted stem cell-deficient W/W(v) mouse recipients. However, only XSCID stem cells transduced with the MFG-S-hIL2RG vector generated B lymphocytes in W/W(v) mice. We conclude that the MFG-S-hIL2RG vector provides the best opportunity for in vivo selection and development of B and T lymphocytes for human XSCID gene therapy.
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PMID:Comparison of five retrovirus vectors containing the human IL-2 receptor gamma chain gene for their ability to restore T and B lymphocytes in the X-linked severe combined immunodeficiency mouse model. 1131 19


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