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)

Interleukin-2 (IL-2), the cytokine also known as T-cell growth factor, has multiple immunoregulatory functions and biological properties not only related to T-cells. In the past decade, substantial evidence accumulated to suggest that IL-2 is also a modulator of neural and neuroendocrine functions. First, extremely potent effects of IL-2 on neural cells were discovered, including activities related to cell growth and survival, transmitter and hormone release and the modulation of bioelectric activities. IL-2 may be involved in the regulation of sleep and arousal, memory function, locomotion and the modulation of the neuroendocrine axis. Second, the concept that IL-2 could act as a neuroregulatory cytokine has been supported by reports on the presence in rodent and human brain tissues of IL-2-like bioactivity, IL-2-like immunoreactivity, IL-2-like mRNA, IL-2 binding sites, IL-2 receptor (IL-2R alpha) and beta chain mRNA and IL-2R immunoreactivity. IL-2 and/or IL-2R molecules mainly localize to the frontal cortex, septum, striatum, hippocampal formation, hypothalamus, locus coeruleus, cerebellum, the pituitary and fiber tracts, such as the corpus callosum, where they are likely expressed by both neuronal and glial cells. Although the molecular biology of the brain IL-2/IL-2R system (including its relation to IL-15/IL-15R alpha) is not yet fully established by cloning and complete sequencing of all respective components, similarities (and to some extent differences) to peripheral counterparts are now apparent. The ability of IL-2 to readily penetrate the blood-brain barrier further suggests that this cytokine could regulate interactions between peripheral tissues and the central nervous system. Taken together, these data suggest that IL-2 of either immune and CNS origin can have access to functional IL-2R molecules on neurons and glia under normal conditions. Additionally, dysregulation of the IL-2/IL-2 receptor system could lead or contribute to functional and pathological alterations in the brain as in the immune system. Understanding the neurobiology of the IL-2/IL-2 receptor system should also help to explain neurologic, neuropsychiatric and neuroendocrine side effects occurring during IL-2 treatment of peripheral and brain tumors. Immunopharmacological manipulation either aiming at the activation or suppression of IL-2 signaling should consider functional interference with constitutive and inducible IL-2 receptors on brain cells in order to fulfil the high expectations associated with the use of this cytokine as a promising agent in immunotherapies, especially of brain tumors.
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PMID:Interleukin-2 as a neuroregulatory cytokine. 880 16

The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.
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PMID:Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4. 892 63

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (beta) and the p64 (gamma) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R beta and gamma molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R gamma-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited by antibodies against p75 and p64 IL-2R chains, while no inhibitory effects are detectable with anti-p55 IL-2R antibody. The association of anti-p75 and anti-p64 IL-2R MoAbs resulted in a nearly complete (95%) inhibition of IL-15-induced GL proliferation. Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2. By contrast, a clear-cut IL-15 mRNA signal was detected by RT-PCR in patients' peripheral blood mononuclear cells, with monocytes likely accounting for the source of IL-15 in LDGL patients. However, even in concentrated supernatants from enriched monocyte populations, we could not demonstrate the presence of IL-15 protein. Using anti-IL-15 specific MoAbs, a membrane-bound form of this cytokine was demonstrated both on CD3+ and CD3- LDGL cells. By RT-PCR analysis, purified GL from these patients were found to express the message for IL-15 receptor alpha chain. Taken together, these results indicate that both CD3+ and CD3- GL are stimulated by IL-15 and that this cytokine mediates its activity through the beta and gamma chains of the IL-2R, providing further suggestions for the interpretation of the mechanisms that lead to cell expansion in patients with LDGL.
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PMID:Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. 897 93

In the current study, we investigated the role of interleukin-2 (IL-2) and IL-4 as autocrine growth factors responsible for autonomous growth of four murine tumor cell lines: LSA, a radiation leukemia virus-induced T-cell lymphoma; EL-4, a chemically triggered T-cell lymphoma; PE-3T, a T-cell line that underwent spontaneous transformation ex vivo; and P815, a mastocytoma. All tumor cell lines screened constitutively expressed IL-2 receptor (IL-2R) and IL-4R genes. However, only LSA and PE-3T cells expressed IL-2 and IL-4 genes constitutively, whereas EL-4 and P815 tumor cells expressed only IL-4 but not IL-2. Monoclonal antibodies (MoAbs) against IL-2, IL-4, or a combination of these, as well as MoAbs against IL-2R significantly inhibited the proliferation of LSA but not that of other tumor cell lines ex vivo. To exclude the possibility that, in other tumor cell lines, the autocrine growth factor may interact with its receptor within the cell, the ability of antisense phosphorothioate oligonucleotides to inhibit the growth of the tumor cells was tested. The antisense phosphorothioate oligonucleotides specific for IL-2, IL-4, IL-2R beta, or IL-2R gamma chains, added in culture, could markedly inhibit the growth of LSA but not that of the other tumor cell lines screened. Inasmuch as IL-2R beta and IL-2R gamma subunits also serve as a component of the receptors for IL-4, IL-7, IL-9, and IL-15, the above data suggested that such cytokine redundancy was not responsible for autonomous growth of the other tumor cell lines. Addition of exogenous IL-2 or IL-4 to the tumor cell cultures caused significant enhancement in the proliferation of PE-3T cells, whereas other cell lines were either not significantly affected or slightly inhibited from growing. Interestingly, the LSA tumor growth in nude mice was significantly inhibited after treatment of these mice with a combination of MoAbs against IL-2 and IL-4. Together, our studies show for the first time that IL-2 and IL-4 may serve as autocrine growth factors in the autonomous proliferation of tumor cells, particularly those that are retrovirally induced. Second, some tumor cell lines, despite expressing certain cytokines and their receptors constitutively, may not depend exclusively on such factors for autocrine growth.
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PMID:Evidence for the participation of interleukin-2 (IL-2) and IL-4 in the regulation of autonomous growth and tumorigenesis of transformed cells of lymphoid origin. 900 65

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.
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PMID:Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. 902 22

Resting lymphocyte survival is dependent upon the expression of Bcl-2, yet the factors responsible for maintaining lymphocyte Bcl-2 protein expression in vivo are largely unknown. Natural killer (NK) cells are bone marrow-derived lymphocytes that constitutively express the beta and common gamma(c) subunits of the IL-2 receptor (R) as a heterodimer with intermediate affinity for IL-2. IL-15 also binds to IL-2Rbeta gamma(c) and is much more abundant in normal tissues than IL-2. Mice that lack the IL-2 gene have NK cells, whereas mice and humans that lack IL-2R gamma(c) do not have NK cells. Further, treatment of mice with an antibody directed against IL-2Rbeta results in a loss of the NK cell compartment. These data suggest that a cytokine other than IL-2, which binds to IL-2Rbeta gamma(c), is important for NK cell development and survival in vivo. In the current report, we show that the recently described IL-15R(alpha) subunit cooperates with IL-2Rbeta gamma(c) to transduce an intracellular signal at picomolar concentrations of IL-15. We demonstrate that resting human NK cells express IL-15R(alpha) mRNA and further, that picomolar amounts of IL-15 can sustain NK cell survival for up to 8 d in the absence of serum. NK cell survival was not sustained by other monocyte-derived factors (i.e., TNF-alpha, IL-1beta, IL-10, IL-12) nor by cytokines known to use gamma(c) for signaling (i.e., IL-4, IL-7, IL-9, IL- 13). One mechanism by which IL-15 promotes NK cell survival may involve the maintenance of Bcl-2 protein expression. Considering these functional properties of IL-15 and the fact that it is produced by bone marrow stromal cells and activated monocytes, we propose that IL-15 may function as an NK cell survival factor in vivo.
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PMID:A potential role for interleukin-15 in the regulation of human natural killer cell survival. 906 51

IL-2 receptor (IL-2R) is composed of three subunits named IL-2R alpha, IL-2R gamma. Here, we study the expression of the IL-2R gamma in highly purified, resting peripheral human CD4 T lymphocytes. We show by FACS analysis that the IL-2R gamma subunit is not detectable at the cell surface of peripheral CD4 T lymphocytes. This result has been verified after acid treatment of the cell surface and analysis with three specific anti-IL-2R gamma mAb. Using RT-PCR and intracellular FACS analysis, we demonstrate that IL-2R gamma is constitutively expressed at the mRNA level and the protein is stored as an intracellular component in resting CD4 T lymphocytes. IL-2R alpha and beta subunits are not detectable by these methods. In addition, we show that CD4 T cell remain insensitive to a variety of cytokines that share IL-2R gamma as a common subunit of their receptors (e.g. IL-2, IL-4, IL-7 and IL-15). The kinetics of cell surface expression of IL-2R gamma have been studied after activation of CD4 T lymphocytes and compared with induction of IL-2R alpha and IL-2R beta. Maximum expression of IL-2R gamma is observed after 2 days of stimulation, and remains constant and comparable to IL-2R beta up to day 5. We conclude from these studies that IL-2R gamma is translocated to the membrane only after T cell activation and induction of the IL-2R alpha and IL-2R beta genes. We hypothesize that in CD4 T cells a large intracellular pool of IL-2R gamma is present but that its cell surface translocation depends on the expression of alpha and/or beta chains specific for IL-2, IL-4, IL-7, IL-9 or IL-15.
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PMID:Expression of the IL-2 receptor gamma subunit in resting human CD4 T lymphocytes: mRNA is constitutively transcribed and the protein stored as an intracellular component. 913 18

The interleukin-2 IL-2 receptor beta-chain (IL-2Rbeta) is an essential component of the receptors for IL-2 and IL-15. Although IL-2Rbeta is constitutively expressed by lymphocytes, its expression can be further induced by a number of stimuli, including phorbol 12-myristate 13-acetate (PMA). We have now characterized factors that bind to an enhancer region located between nucleotides -170 and -139 of the human IL-2Rbeta promoter. Both Sp1 and Sp3 bound to the 5' portion of this region, whereas a PMA-inducible factor (PIF) mainly bound to its 3' portion and bound to the Sp binding motifs as well. In Jurkat T cells, induction of PIF DNA binding activity was rapidly induced, required de novo protein synthesis, and was sustained at a high level for at least 23 h. Interestingly, PIF was constitutively activated in human T-cell leukemia virus type 1-transformed MT-2 cells. In this paper, we demonstrate that PIF is Egr-1 based on its recognition by anti-Egr-1 antisera in gel mobility shift assays, even though the IL-2Rbeta DNA binding motif differed substantially from the canonical Egr-1 binding site. In addition, Egr-1 bound to the Sp binding site. In Jurkat cells, both sites were required for maximal IL-2Rbeta promoter activity, and in HeLaS3 cells, transfection of Egr-1 could drive activity of a reporter construct containing both sites. Moreover, Sp1 and Egr-1 could form a complex with kinetics that correlated with the production of Egr-1 in Jurkat cells upon PMA stimulation. Thus, Sp1 and Egr-1 physically and functionally cooperate to mediate maximal IL-2Rbeta promoter activity.
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PMID:The immediate-early gene product Egr-1 regulates the human interleukin-2 receptor beta-chain promoter through noncanonical Egr and Sp1 binding sites. 919 5

Several tyrosine kinases such as Jak1, Jak3, Lck and Syk are known to participate in IL-2-mediated intracellular signal transduction. Jak1, Lck and Syk are associated with the cytoplasmic domain of the beta chain, whereas Jak3 is associated with the cytoplasmic domain of the gamma chain, which is shared among receptors for IL-2, IL-4, IL-7 and IL-15. We first demonstrated that Jak1 is associated with the alpha chains of receptors for IL-4, IL-7 and IL-15 as well as the IL-2 receptor beta chain. Furthermore, we revealed that two proline residues in the box1 region, which is conserved in the IL-2 receptor beta chain and the alpha chains of the cytokine receptors, are essentially involved in association with Jak1. The MOLT4 transfectants with the box1 mutants of the IL-2 receptor beta chain lacking Jak1 association showed IL-2 responsiveness, in terms of activations of Jak3 and Stat5 and induction of cell growth, indicating that Jak1 is dispensable for IL-2-mediated cell growth signaling, and that Jak1 activation is not required for activation of Jak3 and Stat5 in the MOLT4 transfectants.
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PMID:Regulation of IL-2 signaling. 920 10

The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the beta and gamma chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15R alpha. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2R beta/IL-2R gamma complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-alpha upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti-IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell-mediated immune response.
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PMID:Interleukin-15 triggers activation and growth of the CD8 T-cell pool in extravascular tissues of patients with acquired immunodeficiency syndrome. 924 43

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