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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) has been shown to stimulate tyrosine phosphorylation of a number of proteins requiring only the p75 beta chain of the IL-2 receptor. Unlike the receptors for epidermal growth factor, insulin, and other growth factors, the p55-alpha and p75-beta chains of the IL-2 receptor have no tyrosine protein kinase domain suggesting that the IL-2 receptor complex activates protein kinases by a unique mechanism. The activation of tyrosine kinases by IL-2 in situ was studied and using a novel methodology has shown tyrosine kinase activity associated with the purified IL-2R complex in vitro. IL-2 stimulated the in situ tyrosine phosphorylation of 97 kDa and 58 kDa proteins which bound to poly(Glu,Tyr)4:1, a substrate for tyrosine protein kinases, suggesting these proteins had characteristics found in almost all tyrosine kinases. IL-2 was found to stimulate tyrosine protein kinase activity in receptor extracts partially purified from human T lymphocytes and the YT cell line. Biotinylated IL-2 was used to precipitate the high-affinity-receptor complex and phosphoproteins associated with it. The data indicated that the 97-kDa and 58-kDa phosphotyrosyl proteins were tightly associated with the IL-2 receptor complex. These proteins were phosphorylated on tyrosine residues by IL-2 stimulation of intact cells and ligand treatment of in vitro receptor extracts. Furthermore, the 97-kDa and 58-kDa proteins were found in streptavidin-agarose/biotinylated IL-2 purified receptor preparations and showed high affinity for tyrosine kinase substrate support matrixes. The experiments suggest that these two proteins are potential candidates for tyrosine kinases involved in the IL-2R complex signal transduction process.
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PMID:Regulation of the interleukin 2 receptor complex tyrosine kinase activity in vitro. 175 80

The in vitro effect of synthetic human growth hormone-releasing hormone (GHRH) on mitogen-induced lymphocyte proliferation and lymphokine secretion was investigated. Peripheral blood mononuclear cells (PBMC) of healthy adults were incubated in the presence and absence of increasing concentrations (from 0.006 to 50 micrograms/ml) of two forms of GHRH differing in amino-acid sequence (GHRH 1-44 and GHRH 1-29) or of increasing concentrations (from 0.0012 to 20 U/ml) of recombinant human insulin (rh-insulin). Low concentrations of GHRH 1-29 increased phytoemoagglutinin (PHA)-induced lymphoproliferation, while high concentrations inhibited lymphocyte response, interleukin-2 (IL-2) secretion and IL-2 receptor expression on activated cells. A toxic effect was excluded since no differences in cell viability were observed between cells cultured with and without hormone. GHRH 1-44 did not affect PHA-induced lymphoproliferation, IL-2 production and IL-2 receptor expression. Low concentrations of rh-insulin increased PHA-elicited lymphoproliferation, while high concentrations did not decrease lymphocyte response. The present study suggests that GHRH modulates in vitro human T lymphocyte functions.
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PMID:Influence of growth hormone-releasing hormone (GHRH) on phytohemagglutinin-induced lymphocyte activation: comparison of two synthetic forms. GHRH and PHA-induced lymphocyte activation. 183 62

Insulin has been shown to enhance the proliferation and differentiation of T cells stimulated by both polyclonal stimulants and specific antigen. This study describes an experimental system designed to understand the mechanism(s) by which occupancy of the insulin receptor mediates the enhancement seen in T cell expansion. These experiments demonstrate that the ability of insulin to influence T cell expansion resides in an insulin-mediated maintenance of the interleukin-2 (IL-2) responsiveness of the activated cells. This was analyzed by following the decay pattern of T cell IL-2 responsiveness by placing the activated T cells into serum-free cultures in the presence or absence of insulin. This maintenance of responsiveness was not mediated by insulin regulating the expression of the IL-2 receptor alpha chain. We feel that this experimental approach will prove useful for dissecting the biochemical and molecular changes mediated by insulin which interface with the ability of activated T cells to effectively respond to IL-2.
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PMID:Insulin modulates the interleukin 2 responsiveness of T lymphocytes. 215 Sep 18

The fact that insulitis occurs also in normoglycaemic BB rats led us to investigate the phenotypes of lymphocytes invading the pancreatic islets of prediabetic BB/OK rats in comparison to age- and sex-matched normoglycaemic animals in a retrospective analysis. By using a panel of monoclonal antibodies we investigated the number of pan T-cells, T-helper cells, cytotoxic T-cells and NK-cells and determined the number of activated cells by measurement of class I, class II and IL-2 receptor positive cells. The bound primary antibodies were visualized using the APAAP-technique. The prediabetic rats showed a significantly decreased pancreatic insulin content which was drastically reduced at diagnosis of diabetes. This was accompanied by reduction of the B-cell volume density. The prediabetic as well as the long-term normoglycaemic BB rats showed an accumulation of mononuclear cells (all phenotypes investigated) within the pancreatic islets. Concerning the phenotypes of infiltrating cells there was no qualitative difference between long-term normoglycaemic and prediabetic rats but quantitatively an enhanced amount of W3/25+, OX-8+, OX-6+ and ART-18+ cells could be observed in the prediabetic animals. From our results we conclude that an immunological B-cell destructive process occurs also in long-term normoglycaemic BB rats by participation of mononuclear cells qualitatively not different from those observed in prediabetic animals. Activated T-cells (OX-19+, OX-8+, W3/25+) expressing class II antigens (OX-6+) and the IL-2 receptor (ART-18+) seem to play a significant role in the amplified immunological pancreatic B-cell destruction.
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PMID:Different lymphocyte subset distribution within "insulitis" islets of normoglycaemic and prediabetic BB/OK rats of similar age. 218 40

Seventy patients aged 15-40 yr with recent-onset insulin-dependent diabetes mellitus (IDDM) were entered into a double-blind trial, in which they were randomly assigned to either cyclosporin (7.5 mg.kg-1.day-1) or to placebo and were monitored for 1 yr for various phenotypic and functional parameters of T-lymphocyte-mediated immunity. Before treatment, the proportions of total T-lymphocytes (CD3+) and helper-inducer T-lymphocytes (CD4+) were normal, whereas significantly decreased values of suppressor/cytotoxic T-lymphocytes (CD8+), as compared with normal controls, were found in 31% of the patients. The interleukin 2 (IL-2)-receptor expression was significantly increased in IDDM patients compared with control subjects, although the single values were low: patients, 2.02 +/- 0.41%; controls, 0.88 +/- 0.25% (means +/- SE). Circulating levels of soluble IL-2 receptor were also significantly increased in IDDM patients compared with controls: patients, 372.3 +/- 25.4 U/ml; controls, 235.5 +/- 29.3 U/ml (means +/- SE). However, no major abnormalities were found in mitogen (phytohemagglutinin)-induced IL-2 production, cell proliferation, or IL-2-receptor expression. After 6 mo of cyclosporin treatment, no major modifications of any of the parameters analyzed were noted, even in patients who had cyclosporin blood trough levels greater than 300 ng/ml, i.e., the threshold value associated with clinical efficacy. One explanation for the absence of a major effect of cyclosporin, in contrast with its demonstrated clinical effectiveness, is the reversibility of its activity. Our results preclude the use of the described tests to reliably monitor IDDM patients undergoing immunosuppressive therapy.
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PMID:Effect of cyclosporin on interleukin 2-related T-lymphocyte parameters in IDDM patients. 264 44

We studied interleukin 1 (IL-1) and interleukin 2 (IL-2) production in unstimulated and stimulated cultures from 27 young diabetic patients and 21 age-matched healthy subjects. In unstimulated cultures monocytes from newly diagnosed patients produced significantly higher levels of IL-1 than controls. In lipopolysaccharide (LPS)-stimulated cultures, IL-1 production in patients with fresh and long-standing diabetes was no different from that of controls. IL-2 production was low or absent in unstimulated cultures from insulin-dependent diabetes mellitus (IDDM) patients and controls. In phytohaemagglutinin (PHA)-stimulated cultures both patient groups produced significantly less IL-2 than controls. No correlation was observed between IL-1, IL-2 production and HbA1 levels or the presence of HLA-DR3 or DR4. Our data on "spontaneous" IL-1 production support the hypothesis that monocytes from some newly diagnosed IDDM patients may circulate in a "preactivated" state. The low levels of IL-2 might be explained by an abnormal consumption or by the presence of increased soluble IL-2 receptor levels or by a serum factor which interferes with IL-2 production. Alternatively, it may be a genetically determined trait.
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PMID:Alterations of in vitro interleukin 1 and 2 in diabetic children. 279 22

Alterations in T-lymphocyte subsets have been connected to the autoimmune pathogenesis of Type 1 (insulin-dependent) diabetes. In this study peripheral blood lymphocytes were analysed by flow cytometry using OKT3, OKT4, OKT8, anti-HLA-DR, anti-IL-2 receptor and anti-membrane immunoglobulin antibodies in newly diagnosed Type 1 diabetic children, their healthy siblings and healthy control children. The results were compared to the occurrence of serologically verified recent virus infections, some of which can induce lymphocyte subset alterations and have also been connected with the onset of diabetes. In most diabetic patients the amounts of OKT3, OKT4, OKT8 and membrane-Ig-positive cells were within the normal range. Exceptional helper/inducer and suppressor/cytotoxic T cell profiles were observed in a few patients, most of whom had serologically verified recent Epstein-Barr, rubella, mumps or Coxsackie B virus infection. In addition, increased numbers of activated IL-2 receptor-positive cells were observed in the patient group. These results suggest that significant lymphocyte subset alterations are not characteristic of Type 1 diabetes but can occasionally be induced by recent virus infections in newly diagnosed patients. However, the slight increase in activated lymphocytes could reflect the activation of cellular immune systems to the autoantigens in the pancreas.
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PMID:Flow-cytometric analysis of lymphocyte subsets in relation to virus infections at the onset of type 1 (insulin-dependent) diabetes. 284 9

Twenty-five recently diagnosed insulin-dependent diabetic patients were screened for the presence of activated T lymphocytes using the anti-IL-2 receptor monoclonal antibody; thirteen had elevated levels of activated T lymphocytes. The activated cells were mostly confined to the CD4 subset, with the CD4/CD8 ratio in IL-2 receptor expressing cells averaging 5 +/- 1 (s.d.) compared with 1.3 +/- 0.3 for all T cells. In recent onset insulin-dependent diabetes blood there was no lack of CD4 CD45R+ (suppressor/inducer) T cells. The activated IL-2 receptor, expressing cells belonged to both CD4 subsets, 'helper inducer' (CD44B4) and 'suppressor inducer', (CD42H4).
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PMID:The majority of the activated T cells in the blood of insulin-dependent diabetes mellitus (IDDM) patients are CD4+. 297 27

The expression of activation antigens (transferrin receptor, IL-2 receptor and Ia antigen) on circulating T lymphocytes from Japanese children with Type 1 diabetes was studied using five monoclonal antibodies (Ab), OKT9, anti-Tac Ab, OKIa1, anti-human HLA-DR Ab and OKT3. For detecting Ia positive T cells, the dual staining technique using OKT3 and anti-Ia antibody was employed. Four out of six patients (67%) with newly diagnosed Type 1 diabetes showed a raised level of either OKT9 or Tac positive cells when examined at diagnosis. These patients, however, rapidly lost these activation antigens after the insulin therapy was started. In contrast, in 32 long-standing patients, only 2 (6%) had a high percentage of OKT9 positive cells and none of them demonstrated Tac positive cells. One out of six newly diagnosed patients or three out of 21 long-standing patients had a significantly high percentage of Ia-positive T cells compared with normal subjects. In poorly controlled long-standing patients whose HbA1 value was higher than 14%, none of them had an increased number of activated lymphocytes. Therefore, it is unlikely that insulin deficiency and hyperglycemia were responsible for the changes observed in these studies. Activated lymphocytes might be related to activation of the immune system involved in pathogenesis of Type 1 diabetes.
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PMID:Activated lymphocytes in patients with newly diagnosed type 1 (insulin-dependent) diabetes mellitus. 309 6

In this study both a ligand-dependent treatment [concanavalin A (Con A)] and a ligand-independent treatment [high-voltage pulsed galvanic stimulation (HVPGS)] have been used to initiate lymphocyte activation via a transmembrane signaling process. Our results show that both treatments cause the exposure of two different hormone [insulin and interleukin-2 (IL-2)] receptors within the first 5 min of stimulation. When either insulin or IL-2 is present in the culture medium, the stimulated lymphocytes undergo the following responses: (1) increased free intracellular Ca2+ activity; (2) aggregation of insulin or IL-2 receptors into patch/cap structures; (3) tyrosine-kinase-specific phosphorylation of a 32-kd membrane protein; and finally (4) induction of DNA synthesis. Further analysis indicates that hormone receptor capping is inhibited by (1) cytochalasin D, suggesting the involvement of microfilaments; (2) sodium azide, indicating a requirement for ATP production; and (3) W-5, W-7, and W-12 drugs, implying a need for Ca2+/calmodulin activity. Treatment with these metabolic or cytoskeletal inhibitors also prevents both the tyrosine-kinase-specific protein phosphorylation and DNA synthesis which normally follow hormone receptor capping. Double immunofluorescence staining shows that actomyosin, Ca2+/calmodulin, and myosin light-chain kinase are all closely associated with the insulin and IL-2 receptor cap structures. These findings strongly suggest that an actomyosin-mediated contractile system (regulated by Ca2+, calmodulin, and myosin light-chain kinase in an energy-dependent manner) is required not only for the collection of insulin and IL-2 receptors into patch and cap structures but also for the subsequent activation of tyrosine kinase and the initiation of DNA synthesis. We, therefore, propose that the exposure and subsequent patching/capping of at least one hormone receptor are required for the activation of mouse splenic T-lymphocytes.
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PMID:Lymphocyte activation and capping of hormone receptors. 313 94


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