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)

There has been interest in the potential of synthetic compounds to modify immune responses by imitation of cytokine action. Direct administration of interleukin 2 (IL-2) in conjunction with adoptive transfer of lymphokine activated killer cells has been used in the treatment of cancer, but there are toxic effects resulting from the high doses of IL-2 required. We have developed a new synthetic compound, ammonium tri-chloro(dioxoethylene-O,O'-)tellurate (AS-101), which has immunomodulating properties and minimal toxicity. The effects of AS-101 on the activation and function of immunocompetent cells have been assessed. We have found that AS-101 induces proliferation and IL-2 production by human lymphocytes in vitro, and enhances the production of IL-2 and colony-stimulating factor by mouse spleen cells. Splenocytes of BALB/c mice injected with AS-101 increased production of IL-2 and CSF in vitro in the presence of mitogen. Mononuclear cells of normal donors acquired responsiveness to recombinant IL-2 and bound monoclonal antibody to IL-2 receptor after incubation with AS-101. Splenocytes of mice treated in vivo with AS-101 expressed high levels of IL-2 receptor. The stimulation of lymphocytes by AS-101 apparently involves an increase in intracellular free calcium. AS-101 administered systemically to mice mediated antitumour effects which could be attributable to its immunomodulatory properties. In addition, AS-101 could directly enhance the ratio of OKT4 to OKT8-positive cells in cultured mononuclear cells from AIDS (acquired immune deficiency syndrome) patients. These results indicate that AS-101 is potentially useful in the treatment of clinical conditions involving immunosuppression.
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PMID:A new immunomodulating compound (AS-101) with potential therapeutic application. 311 16

Human lymphocytes can respond to interleukin 2 (IL-2) under serum-free conditions with generation of major histocompatibility locus-unrestricted oncolytic activity. This function has been named lymphokine activated killing (LAK). Although IL-2 is sufficient for the development of LAK, this function can be regulated positively by the addition of tumor necrosis factor alpha or beta (TNF-alpha or -beta). The cytotoxic synergy observed with TNF enables production of optimal LAK function at a 10-fold lower IL-2 concentration. Neither TNF-alpha nor -beta is able to induce LAK function in the absence of IL-2. Using TNF-alpha as a model, we demonstrate that (a) the cytotoxic synergy occurs with both fresh human tumors and cell lines; (b) the degree of IL-2/TNF-alpha synergy, for most peripheral blood lymphocyte donors, is dependent upon the IL-2 concentration used for activation with the most striking synergy observed at lower IL-2 doses; (c) synergy is specific for TNF-alpha and can be abrogated by neutralizing antibody against this cytokine; (d) addition of high-dose neutralizing antibody to IL-2 alone-stimulated peripheral blood lymphocytes can reduce the cytotoxicity capacity of these effectors suggesting an immunoregulatory role for endogenous TNF-alpha; and (e) TNF-alpha addition to IL-2-stimulated peripheral blood lymphocytes does not increase proliferation or cell recovery but does result in enhanced IL-2 receptor expression. Collectively, our results suggest that TNF-alpha (and -beta) have immunopotentiating roles in the amplification of non-major histocompatibility locus-restricted lymphocyte effector function.
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PMID:Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor alpha and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity. 325 8

Recombinant human interleukin 6 (IL-6), also termed B-cell-stimulatory factor 2 (BSF-2) or interferon-beta 2, was found to stimulate the proliferation of mouse thymocytes costimulated with phytohemagglutinin (PHA). In addition, IL-6 synergistically enhanced the stimulation of thymocyte proliferation by recombinant human interleukin 1 (IL-1) or interleukin 2 (IL-2). Mature thymocytes lacking peanut agglutinin receptor are the main target of IL-6 action. Incubation of thymocytes with IL-6 in the presence of PHA resulted in an increased expression of the IL-2 receptor (IL-2R) as demonstrated by flow cytometry. Monoclonal antibody specific for the p55 chain of the murine IL-2R significantly reduced IL-6-stimulated thymocyte proliferation in the presence of the optimal concentration of PHA. However, the same monoclonal antibody failed to reduce IL-6-driven thymocyte proliferation in the presence of a suboptimal PHA concentration, suggesting that IL-6 stimulates thymocyte proliferation by way of IL-2-dependent and IL-2-independent pathways. These results indicate that, in addition to its earlier demonstrated ability to promote B-cell differentiation and growth, IL-6 also acts as a growth regulator in cells of the T-lymphocyte lineage. IL-6 is emerging as an important regulatory cytokine with multiple actions on immune functions.
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PMID:Interleukin 2-dependent and interleukin 2-independent pathways of regulation of thymocyte function by interleukin 6. 326 51

Recently, the presence of a soluble form of IL-2 receptor (IL-2RS) in human sera and in supernatants of PHA-stimulated lymphocytes has been demonstrated. It has been suggested that autoimmune diseases could be characterized by a defect in production of IL-2RS, unlike immunoproliferative disorders which are characterized by overproduction. Our aim was to investigate serum IL-2RS levels in 35 newly diagnosed Type 1 diabetic patients, in 25 age-matched healthy blood donors and in five patients with Hodgkin's disease. We found that newly diagnosed diabetic patients have higher IL-2RS levels (424.8 +/- 203 U/ml) than normal controls (252.4 +/- 38.4 U/ml) (p less than 0.005). In 22 out of 35 patients (62.8%) the IL-2RS values were above the higher 95% tolerance limit of controls. Furthermore, the persistence of high IL-2RS levels was observed in 18/35 diabetic patients six months after diagnosis (470 +/- 195.6 U/ml). The increased levels were not correlated with glycaemic and HbA1c levels and patients' age. Our findings suggest a potentially significant role for the released IL-2R in the regulation of IL-2 dependent lymphocyte functions in Type 1 diabetes. The study of IL-2RS in Type 1 diabetes may provide a new tool for the knowledge of cytokine involvement in the disease.
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PMID:Increased soluble interleukin-2 receptor levels in the sera of type 1 diabetic patients. 326 1

The ability of peripheral blood mononuclear cells (PBMC) to produce and respond to interleukin-2 (IL-2) was evaluated in 50 recipients of HLA-identical bone marrow (BM) depleted of mature T cells by soybean agglutination and E rosetting (SBA-E-BM). In contrast to our previous findings in recipients of unfractionated marrow, during weeks 3 to 7 post-SBA-E-BM transplantation (BMT), PBMC from the majority of patients spontaneously released IL-2 into the culture medium. This IL-2 was not produced by Leu-11+ natural killer cells, which were found to be predominant in the circulation at this time, but by T11+, T3+, Ia antigen-bearing T cells. The IL-2 production could be enhanced by coculture with host PBMC frozen before transplant but not by stimulation with mitogenic amounts of OKT3 antibody, thus suggesting an in vivo activation of donor T cells or their precursors by host tissue. Spontaneous IL-2 production was inversely proportional to the number of circulating peripheral blood lymphocytes and ceased after 7 to 8 weeks post-SBA-E-BMT in most of the patients. In patients whose cells had ceased to produce IL-2 spontaneously or never produced this cytokine, neither coculture with host cells nor stimulation with OKT3 antibody thereafter induced IL-2 release through the first year posttransplant. Proliferative responses to exogenous IL-2 after stimulation with OKT3 antibody remained abnormal for up to 6 months post-SBA-E-BMT, unlike the responses of PBMC from recipients of conventional BM, which responded normally by 1 month post-BMT. However, the upregulation of IL-2 receptor expression by exogenous IL-2 was found to be comparable to normal controls when tested as early as 3 weeks post-SBA-E-BMT. Therefore, the immunologic recovery of proliferative responses to IL-2 and the appearance of cells regulating in vivo activation of T cells appear to be more delayed in patients receiving T cell-depleted BMT. Similar to patients receiving conventional BMT, however, the ability to produce IL-2 after mitogenic stimulation remains depressed for up to 1 year after transplantation.
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PMID:Interleukin-2 production and response to interleukin-2 by peripheral blood mononuclear cells from patients after bone marrow transplantation: II. Patients receiving soybean lectin-separated and T cell-depleted bone marrow. 331 Dec 8

Cytokine mRNA expression was analyzed by reverse transcriptase (RT)/PCR in extensively purified normal peripheral CD4+CD45R T cell subsets. Both CD45RA+ and CD45 RO+ populations produced mRNAs for interleukin (IL)-2, IL-2 receptor (alpha chain), IL-6 receptor and tumour necrosis factor (TNF)-beta within 3-4 h of activation. Whilst IL-3 and RANTES were also expressed in both subsets, CD45RO+ cells were clearly the major producers of these cytokines. In contrast, mRNA transcripts for IL-1 alpha, IL-4, IL-5, IL-6, IL-10, interferon gamma (IFN-gamma) and the T cell receptor for IL-1 were almost exclusively induced in CD45RO+ T cells. A population of CD4+ T cells co-expressing intermediate levels of both CD45RA and CD45RO, namely CD45RA+/CD45RO+, appeared to be the major producers of IL-6. Addition of cycloheximide (CHx) 4 h after T cell activation resulted in substantial superinduction of IL-2 mRNA in the CD4+CD45RO+ population but had little effect on CD4+CD45RA+ cells. Taken together, these results show that normal CD4+CD45R T cell subsets exhibit distinct cytokine mRNA profiles and that these differ from the patterns displayed by Th1 and Th2 type T helper clones. Furthermore, they suggest for the first time that IL-2 mRNA turnover is differentially regulated in CD45R T cell subsets.
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PMID:Differential expression and regulation of cytokine mRNAs in normal human CD45R T cell subsets. 751 60

Janus tyrosine kinase (JAK) has recently been linked to signal transduction by cytokine receptors of the hematopoietin family. We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase. These included receptor association, rapid and transient tyrosine phosphorylation kinetics in response to ligand, and in vitro autophosphorylating tyrosine kinase activity (Kirken, R. A., Rui, H., Evans, G. A., and Farrar, W. L. (1993) J. Biol. Chem. 268, 22765-22770). Here we extend these observations by demonstrating structural homologies between IL-2-modulated p116 and prolactin-modulated JAK2 in the rat T cell line Nb2. These include similar net charge as determined by nonequilibrium pH gradient electrofocusing and related primary structure based upon phosphopeptide mapping of V8 protease-digested hyperphosphorylated proteins. This putative JAK kinase underwent marked tyrosine phosphorylation in response to IL-2, IL-4, and IL-7, lymphoid growth factors that use the common IL-2 receptor gamma-chain, but not in response to prolactin. Furthermore, polyclonal antisera to JAK1, JAK2, or tyrosine kinase 2 did not recognize either rat or human p116. However, we identified the IL-2-modulated p116 as the recently cloned novel leukocyte Janus kinase, L-JAK, using an antiserum to a peptide corresponding to the COOH terminus of human L-JAK.
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PMID:Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. 751 51

Interleukin 15 (IL-15) is a novel cytokine that has recently been cloned and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells. The CD56bright subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R beta (p75), but not by anti-IL-2R alpha (p55). The proliferative effects of IL-2 on CD56bright NK cells could be inhibited by both antibodies. CD56dim NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56dim NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibody-dependent cellular cytotoxicity, and NK cell production of interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-2R beta monoclonal antibody. The binding of radiolabeled IL-2 and IL-15 to CD56dim NK cells was inhibited in the presence of anti-IL-2R beta. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.
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PMID:Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. 752 71

The neuropeptide arginine vasopressin (AVP) can replace the cytokine interleukin 2 (IL-2) as a T-cell mitogen for the induction of interferon gamma (IFN gamma) expression in splenic cultures. IL-2-like and IL-2 receptor immunoreactivity have been reported in different brain regions, under normal and pathophysiological conditions. Regulatory functions for IL-2 in the CNS have been suggested. In addition to the spleen, AVP might also mediate some IL-2 effects centrally. In the present study, we evaluated the effect of IL-2 on the in vitro release of AVP from the hypothalamus and amygdala. In addition, we used these release systems to study the possible involvement of NO-mediated signaling in AVP release, based on the reported detection of nitric oxide synthase (NOS) in the hypothalamus and amygdala. IL-2 rapidly stimulates AVP release in both regions, in a calcium- and dose-dependent manner. In addition, nitroprusside also induces AVP release. Norepinephrine also induces AVP release from both the hypothalamus, as well as the amygdala. The norepinephrine-induced AVP release is antagonized by phentolamine, but not by propranolol, suggesting an alpha-adrenergic receptor-mediated AVP response in both brain regions. The IL-2- and acetylcholine-induced AVP release is antagonized by Ng-methyl-L-arginine, indicating a role for NO in this AVP release. Ng-methyl-L-arginine does not affect the norepinephrine-induced AVP release. A stimulatory effect of IL-2 on hypothalamic CRF release and plasma ACTH has already been reported. Our results suggest that in addition to CRF, AVP may also mediate the IL-2 stimulation of ACTH secretion. These data further suggest that in addition to the hypothalamus, the amygdala may also play a role in the bidirectional communication between neuroendocrine and immune systems. Understanding the mode of interaction between IL-2 with AVP could clarify the pathophysiologic or toxic effects of high brain levels of IL-2.
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PMID:IL-2 induces vasopressin release from the hypothalamus and the amygdala: role of nitric oxide-mediated signaling. 752 33

Cytokine is a generic term of biologically active molecules which are mainly produced by the immune-competent cells and regulate the immune response, inflammation and hematopoiesis. This includes interleukins (IL), colony-stimulating factors (CSF), interferons (IFN), tumor necrosis factors (TNF) and so on. These cytokines are glycoproteins with a molecular weight of 20,000-40,000 kD and work at very low concentrations of pM order. ILs and CSFs transduce their signal via specific cell-membrane receptors which usually consist of at least two subunits and belong to a newly identified superfamily of cytokine receptors. Characterization of cytokine/receptor system has had a considerable impact on many clinical fields including pathophysiology of diseases and therapy. For example, IL-4 and IL-5 has been revealed to play essential roles in IgE production in allergic diseases and eosinophilia in a hypereosinophilic syndrome, respectively. Receptor abnormality has also been proven to cause diseases; patients for X-linked severe combined immunodeficiency (X-SCID) have a specific defect in the gamma chain of the IL-2 receptor which is critical for thymic maturation of T cells. EPO, G-CSF, M-CSF, IFN, and IL-2 are already commercially available for therapeutic use. IL-1, IL-3, IL-6, and TNF may also be useful for mycosis fungoides, aplastic anemia, thrombocytopenia, and malignant melanoma, respectively. On the other hand, it is possible to modulate the immune response by using the monoclonal antibody directed to the cytokine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cytokine and disease]. 752 45


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