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

Interleukin-2 (IL-2) and interleukin-15 (IL-15) are T-cell tropic factors that share beta and gammac subunits of their receptors on T/NK-cells. Although these two cytokines share receptor components, the IL-15Ralpha molecule is expressed constitutively by various tissue cells, whereas the IL-2Ralpha expression is mostly restricted to activated mononuclear cells. Consequently, we postulated that the biodistribution of IL-15 might be different from that of IL-2 and that individual alpha chains play an important role in this respect. This study investigated the differences between IL-2 and IL-15 in pharmacokinetics, biodistribution, and their tumor-targeting abilities. It found that only IL-2 showed specific binding to a protein, alpha2-macroglobulin, which may be the reason that IL-2 displays longer blood clearance than IL-15. Upon injection of these cytokines into mice, we observed that IL-15 accumulated significantly more than IL-2 in kidney, spleen, and bone. These are all tissues that express IL-15 receptor alpha but not IL-2 receptor alpha. To evaluate the tumor-targeting ability of each cytokine, we used nude mice xenografted with three A431 tumors, parental and cells transfected with alpha subunit of the receptor for either IL-2 or IL-15. When examined using radioiodinated IL-2 or IL-15, each cytokine accumulated on the target cells, expressing its respective alpha chain, suggesting that the expression of the alpha chains is sufficient to define specific biodistribution of IL-2 and IL-15, although these cytokines share the beta and yc molecules of their receptors. IL-15 displayed better target-specific accumulation and more rapid clearance from the circulation than did IL-2, and thus it can be considered to be a novel and unique therapeutic agent.
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PMID:Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15. 1091 71

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

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.
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PMID:IL-15 and IL-2: a matter of life and death for T cells in vivo. 1113 25

T cell anergy is characterized by alterations in TCR signaling that may play a role in controlling the unresponsiveness of the anergic cell. We have addressed questions regarding the importance of the Src kinase p59(fyn) (Fyn) in this process by using Fyn null mice. We demonstrate that a mature population of CD4(-)CD8(-) alphabeta TCR(+) anergic T cells lacking Fyn have a substantial recovery of their proliferation defect in response to Ag stimulation. This recovery cannot be explained by ameliorated production of IL-2, and the improved proliferation correlates with an enhanced ability of the Fyn(-/-) anergic T cells to up-regulate the high affinity IL-2 receptor. We also observe that anergic CD4(-)CD8(-) alphabeta TCR(+) T cells have a heightened survival ability that is partially dependent on the elevated levels of Fyn and IL-2 receptor beta-chain expressed by these cells. The enhanced survival correlates with an increased capacity of the anergic cells to respond to IL-15. We conclude that Fyn plays an important role in aspects of T cell anergy pertaining to TCR signaling and to cell survival.
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PMID:p59fyn (Fyn) promotes the survival of anergic CD4-CD8- alpha beta TCR+ cells but negatively regulates their proliferative response to antigen stimulation. 1116 Jan 94

Numerous studies have implicated interleukin-2 (IL-2) in various brain processes, and more recently, several studies have also attributed neurobiological actions to interleukin-15 (IL-15). On lymphocytes, receptors for IL-2 and IL-15 share a common subunit, the IL-2/15 receptor-beta (IL-2/15Rbeta) that is essential for intracellular signaling. Although a short segment of IL-2/15Rbeta has been cloned (0.35 kb) from normal brain cells, attempts to isolate the full-length cDNA have been unsuccessful, suggesting the possibility that the genes expressed by brain cells and lymphocytes may differ. Using conventional and anchored PCR cloning strategies, we isolated the full-length cDNA of IL-2/15Rbeta (2038 bp) from well-perfused, normal mouse forebrain. The coding sequence and the adjacent 5' and 3' UTR sequences from brain and lymphocyte were found to be fully homologous. Although evidence of expression of IL-2/15Rbeta can be found in many brain regions using PCR, clear evidence of gene expression by in situ hybridization was detectable only in the hippocampal formation, habenula and piriform cortex. This same pattern of mRNA expression in situ was also observed for the common gamma subunit shared by IL-2 and IL-15. In the hippocampus, IL-2/15Rbeta expression was localized to neurons by high resolution in situ hybridization and evidence of IL-2 receptor protein expression was also detected by radioligand receptor binding using hippocampal homogenates. Comparison of undifferentiated and differentiated, immortalized H19-7 hippocampal neurons showed that IL-2/15Rbeta was constitutively expressed across disparate stages of hippocampal neuronal differentiation. These data indicate that IL-2/15Rbeta may serve to modulate neuronal processes in the hippocampus and associated limbic brain regions.
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PMID:Cloning the full-length IL-2/15 receptor-beta cDNA sequence from mouse brain: evidence of enrichment in hippocampal formation neurons. 1117 82

IL-2 and -15 belong to the four alpha-helix bundle family of cytokines and display a spectrum of overlapping immune functions because of shared signal transducing receptor components of the IL-2 receptor complex. However, recent evidence suggests a nonredundant unique role for IL-15 in the establishment and perhaps maintenance of peripheral natural killer (NK) cell populations in vivo. To explore the contribution of locally released IL-15 on peripheral NK-cell-mediated innate immune responses, we generated a recombinant vaccinia virus that expresses IL-15 and evaluated the course of vaccinial disease in athymic nude mice. Coexpression of IL-15 resulted in the attenuation of virulence of vaccinia virus, and mice inoculated with 10(5) plaque-forming units or less resolved the infection successfully. In contrast, mice inoculated with a similar dose of the control vaccinia virus failed to eliminate the virus and died of generalized vaccinial disease. Enhanced expression of IL-12 and IFN-gamma as well as induction of chemokines were evident in the mice inoculated with IL-15-expressing vaccinia virus in addition to an increase in NK cells in the spleen. However, in this model system, the degree of attenuation in viral virulence attained with coexpression of IL-15 was much less than that achieved with coexpression of IL-2, suggesting that the peripheral NK-cell-mediated events are more responsive to IL-2 than to IL-15.
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PMID:Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice. 1129 52

Cutaneous T cell lymphomas (CTCLs) often show abnormal interleukin-2 (IL-2) receptor signaling. In this study, we investigated the role of Gab2, a recently identified adaptor molecule involved in IL-2 receptor signaling in CTCLs. We show that Gab2 was transiently phosphorylated by tyrosine in human mycosis fungoides (MF) tumor T cells upon IL-2 stimulation and that SHP2 as well as Stat5a associated inducibly with Gab2. IL-15, but not IL-4, also induced tyrosine phosphorylation of Gab2, suggesting that the IL-2 receptor beta-chain is important for IL-2-induced Gab2 phosphorylation. Preincubation of cells with the Src family kinase inhibitor, PP1, surprisingly increased the IL-2- and IL-15-induced tyrosine phosphorylation of Gab2, indicating that an Src family kinase member negatively regulates IL-2 receptor signaling in MF T cells. Thus, although Gab2 seems to function normally in MF T cells compared to normal T cells, Gab2 itself might be abnormally regulated by an Src family kinase.
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PMID:Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a. 1134 Feb 97

Natural killer (NK) cells play important roles in innate immunity by lysing tumor and virally infected cells and by producing cytokines including interferon-gamma. While NK cell progenitors have been described in the fetal thymus, NK cell generation from hematopoietic stem cells (HSC) in the bone marrow (BM) occurs throughout life, and in athymic mice and humans. Interleukin (IL)-15 promotes NK development in vitro and is essential for the generation of normal numbers of NK cells in vivo. By characterizing BM cells expressing IL-15 receptor components, we found marked heterogeneity within the IL-2 receptor beta chain(+) (CD122(+)) subset, which included cells uniquely committed to the NK lineage. These CD122(+) NK cell precursors (NKP) are negative for markers used to identify mature NK cells, including NK1.1, DX5 and members of Ly-49 family, and fail to demonstrate natural cytotoxicity against susceptible target cells. In vitro culture of NKP generates mature lytic NK1.1(+) cells at high frequencies, while they do not give rise to T, B, myeloid or erythroid cells under appropriate conditions. NKP lack transcripts associated with early B and T cell differentiation (pTalpha, lambda5 and CD3epsilon), but express a group of genes (IL-15Ralpha, Id2, GATA-3 and Ets-1) and the 2B4 marker, which may define NK cell commitment. We propose that NKP represent the earliest adult BM precursor uniquely restricted to the NK cell lineage.
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PMID:Identification of committed NK cell progenitors in adult murine bone marrow. 1143 87

IL-2 and IL-15 have overlapping functions since they share the IL-2Rbetagamma receptor complex. However, each cytokine has a private alpha receptor namely IL-2Ralpha for IL-2 and IL-15Ralpha for IL-15. As a consequence the effects of the two cytokines may differ. We describe the differential effects of the two cytokines regarding the induction of cell surface expression of the IL-2Ralpha subunit on YT-l cells. Both cytokines induced transcription of the IL-2Ralpha gene. Furthermore translation of IL-2Ralpha leading to intracellular expression of the receptor was observed following either IL-2 or IL-15 addition. However, only IL-15 was associated with the induction of cell surface expression of IL-2Ralpha. With IL-2 there appears to be an impediment to the translocation of IL-2Ralpha to the cell membrane. Since surface expression of IL-2Ralpha is a key element in the formation of the high affinity IL-2 receptor, translocation of IL-2Ralpha to the membrane represents another level of control of the immune response in addition to regulation of IL-2Ralpha transcription and translation.
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PMID:Differential effects of IL-2 and IL-15 on expression of IL-2 receptor alpha. 1147 99

The plasma levels of a panel of cytokines and cytokine-associated molecules (IL-1alpha, IL-2, IL-4, IL-6, IL-10, IL-12, IL-15, macrophage colony-stimulating factor (M-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), soluble tumor necrosis factor receptor I or II (sTNFRI or II)) were assessed in 56 plasma samples of 13 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT, bone marrow in 12 and cord blood in one) from unrelated donors. Eight patients developed severe (grade III-IV) acute GVHD (aGVHD). The plasma IL-6, IL-10, M-CSF, sTNFRI and II levels were significantly high in the severe aGVHD group compared to the mild aGVHD group (grade 0-II). The plasma IL-15 level increased transiently in the early period following HSCT and remained high in the severe aGVHD group even after 4 weeks following HSCT. Based on analysis of the correlations between the kinetics of the plasma cytokine levels after HSCT and the clinical manifestations of aGVHD, IL-15 and/or M-CSF were involved in the development of aGVHD, following elevation of the plasma IL-10 and sTNFRI or II levels. These kinetics suggest that IL-10 and sTNFRs worked as suppressor cytokines and seemed to suppress clinical manifestations of aGVHD. Furthermore, it seemed that the plasma ratio of IL-10/sTNFRII from 5 to 12 weeks following HSCT was linked to the poor outcome in the patients with severe aGVHD, suggesting that IL-10 plays an important role in protecting hosts from transplantation-related complications, including GVHD.
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PMID:Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease. 1155 Oct 26


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