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)

T cell lines with specificity for bovine insulin and ovalbumin were maintained by serial stimulation with antigen presented on irradiated syngeneic spleen cells, alternating 3 days later with subculture in IL-2 containing medium (CM). When the cultures were repetitively split in CM, with concomitant dilution of antigen-presenting cells, a gradual loss of proliferative capacity of the cells in the presence of CM was observed. Absorption studies revealed a 20-fold reduction of IL-2 receptors on the surface of T blasts assayed 12 days after antigenic stimulation as compared with day 5 blasts. This decrement in the number of IL-2 acceptor sites reflected an actual decrease in cell surface density of IL-2 receptors. Restimulation of the T blasts with antigen and spleen cells induced both a substantial increase in IL-2 receptor density and responsiveness to CM. Furthermore, the permanent presence of antigen and spleen cells during splitting of the T blasts in CM prevented the loss of responsiveness to IL-2. As an interpretation we propose that the Lyt-1 cells studied here clear their IL-2 receptors from the cell surface after interaction with IL-2. Thus, each new round of replication of the daughter cells would be dependent on induction of IL-2 receptors by activating signals provided by antigen/Ia structures on accessory cells as well as possibly accessory cell products such as IL-1, rendering Lyt-1 cells sensitive to regulatory influences.
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PMID:Perpetual proliferation of LYT-1 cells requires repetitive signals for IL-2 receptor induction by antigen-presenting cells. 642 5

The interleukin (IL)-2 receptor system has previously been shown to signal through the association and tyrosine phosphorylation of Shc. This study demonstrates that the IL-2 receptor beta (IL-2R beta) chain is the critical receptor component required to mediate this effect. The use of IL-2R beta chain deletion mutants transfected into a Ba/F3 murine cell model describes a requirement for the IL-2R beta "acid-rich" domain between amino acids 315 and 384 for Shc tyrosine phosphorylation and receptor association. COS cell co-transfection studies of IL-2R beta chain constructs containing point mutations of tyrosine to phenylalanine along with the tyrosine kinase Jak-1 and a hemagglutinin-tagged Shc revealed that the motif surrounding phosphorylated tyrosine 338 within the acid-rich domain of the IL-2R beta is a binding site for Shc. Deletion of this domain has previously been shown to abrogate the ability of IL-2 to activate Ras but does not affect IL-2-dependent mitogenesis in the presence of serum. Proliferation assays of Ba/F3 cells containing IL-2R beta chain deletion mutants in serum-free medium with or without insulin shows that deletion of the acid-rich domain does not affect IL-2-driven mitogenesis regardless of the culture conditions. This study thus defines the critical domain within the IL-2R beta chain required to mediate Shc binding and Shc tyrosine phosphorylation and further shows that Shc binding and phosphorylation are not required for IL-2-dependent mitogenesis. Neither serum nor insulin is required to supplement the loss of induction of the Shc adapter or Ras pathways, which therefore suggests a novel mechanism for mitogenic signal transduction mediated by this hematopoietin receptor.
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PMID:Analysis of interleukin-2-dependent signal transduction through the Shc/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require Shc phosphorylation or receptor association. 749 11

Protein tyrosine phosphorylation is known to play key roles in lymphocyte signal transduction, and phosphotyrosine phosphatases (PTP) can act as both positive and negative regulators of these lymphocyte signals. We sought to examine the role of PTP further in these processes by characterizing the effects of bis(maltolato)-oxovanadium(IV) (BMLOV), previously known to be a nontoxic insulin mimetic agent in vivo. BMLOV was found to be a potent phosphotyrosine phosphatase inhibitor. BMLOV induced cellular tyrosine phosphorylation in B cells in a pattern similar to that observed following antigen receptor stimulation, whereas little tyrosine phosphorylation was induced in T cells. In B cells, BMLOV treatment resulted in tyrosine phosphorylation of Syk and phospholipase C gamma 2, while sIgM-induced signals were inhibited. By contrast, T cell receptor signals were moderately increased by BMLOV, and the cells displayed greater induction of IL-2 receptor without toxicity. The compound selectively induced apoptosis in B cell lymphoma and myeloid leukemia cell lines, but not in T cell leukemia or colon carcinoma cells. Interleukin-4 plus anti-CD40 antibody treatment of normal human peripheral B cells rescued the cells from BMLOV-induced death. These results suggest that phosphotyrosine phosphatase inhibitors can activate B cell signal pathways in a lineage-specific manner, resulting in desensitization of receptor-mediated signaling and induction of apoptosis.
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PMID:Lineage-specific induction of B cell apoptosis and altered signal transduction by the phosphotyrosine phosphatase inhibitor bis(maltolato)oxovanadium(IV). 765 67

In Type I diabetes the observation of a decreased release of interleukin-2 (IL-2) and soluble IL-2 receptors by means of stimulated lymphocytes in vitro indicates that a primary immunoregulatory defect may be involved. To confirm this hypothesis we investigated the T-cell activation trend, evaluating the surface expression of IL-2 receptor (CD25), transferrin (CD71), HLA class II (DR), and CD69 phenotypes after in vitro stimulation with phytohemagglutinin (PHA; 1 and 10 micrograms/ml) and concanavalin A (12.5 micrograms/ml) in six newly diagnosed Type I diabetics and six islet cell- and insulin autoantibody-positive first-degree relatives. As controls were studied six long-standing Type I diabetics and six healthy subjects. T-cell cultures from the four groups were performed on the same day and examined at 0, 24, 48, 96, 120, and 144 hr. Cytometric analysis was performed, keeping PBMC gating constant on the basis of physical parameters (scatter and volume). Using both PHA concentrations, a lower level of CD25, CD71, CD69, and DR antigen expression was found in newly diagnosed patients at all observation times with respect to control cultures (P < 0.001). Unexpectedly, pre-Type I diabetic subjects, after 1 microgram/ml of PHA, showed a significantly reduced expression of CD69 (P < 0.001) and CD71 (P < 0.001). The levels remained low, also with high PHA, at the different observation periods, while CD25 expression was found to be reduced in prediabetics only after 1 micrograms/ml of PHA (P < 0.001). The long-standing patients showed a T cell activation trend very close to the latter. Our data show that in Type I diabetes and in the early phases of the disease, the initial activation signal(s) appears to be affected, particularly with one or more subsequent events necessary to initiate the appearance of "activation antigens." This study suggests that the natural history of immunoregulation in pre-Type I and Type I diabetes is characterized by a primary defect in this system, which also persists in patients with long-standing disease.
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PMID:Study of T-cell activation in type I diabetic patients and pre-type I diabetic subjects by cytometric analysis: antigen expression defect in vitro. 809 71

Type I, insulin-dependent diabetes (IDD) in both man and animals results from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomonic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histological and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect the functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivities of islet-infiltrating mononuclear cell populations by measuring increased cytokine mRNA usage. Results indicate that 1) cytokine mRNA profiles exhibited by islet-infiltrating cells of female and male NOD mice were quite similar with the exception of IL-6 expression and the marked differences in the levels of IL-2 receptor and IL-1 alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibited TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was expressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural history of autoimmune diabetes. Interestingly, this model, based on a TH2- and not a TH1-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.
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PMID:Insulin-dependent diabetes in the NOD mouse model. II. Beta cell destruction in autoimmune diabetes is a TH2 and not a TH1 mediated event. 810 89

The pathophysiology of psychotic and other symptoms in schizophrenia remains a mystery despite decades of research. Even though it has been suspected for many years that autoimmune mechanisms may play a role in the pathophysiology of schizophrenia, firm evidence for this hypothesis has been lacking. Our studies, over the last 10 years, have revealed that a subgroup of schizophrenics have several significant immunological abnormalities, including increased prevalence of autoimmune diseases and of antinuclear antibodies (ANA) and anticytoplasmic antibodies (ACA), decreased lymphocyte interleukin-2 (IL-2) production, increased serum IL-2 receptor concentration, increased serum IL-6 concentration, and an association with HLA antigens. These findings are characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and insulin-dependent diabetes mellitus. We also found that some schizophrenics have antibodies to hippocampal antigens (AHA) in their serum, together with lowered IL-2 production. None of the above findings can be interpreted as definitely confirming the role of autoimmunity in schizophrenia. Nevertheless, taken together, the recent evidence points towards the existence of a subgroup of schizophrenics who have immunological findings consistent with that hypothesis. Further studies directed at finding the brain antigens targeted by the immune system in these patients, and longitudinal studies correlating clinical and immune changes over time, are needed.
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PMID:Autoimmunity in schizophrenia: a review of recent findings. 825 Nov 50

The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.
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PMID:The mitogenic response of T cells to interleukin-2 requires Raf-1. 825 28

DAB486IL-2 is the first of a new class of targeted biologicals called fusion toxins. This agent is an interleukin-2 receptor (IL-2R)-targeted cytotoxin which kills activated IL-2R-expressing lymphocytes at 10(-10) M concentrations. Since activated lymphocytes are thought to play a role in many autoimmune conditions, DAB486IL-2 has been evaluated in patients with severe rheumatoid arthritis and recent onset autoimmune insulin-dependent diabetes mellitus. Initial safety, pharmacokinetics and evidence of IL-2R specific cytotoxicity were obtained in patients with IL-2 receptor expressing malignancies; these studies served as a basis for the initiation of an open label phase I/II evaluation of DAB486IL-2 in patients with severe, methotrexate refractory rheumatoid arthritis. This pilot study provided preliminary evidence of acceptable safety at doses which induced meaningful (> 25%) or substantial (> 50%) improvement in 9 of 18 patients who received a mid (130 kU/kg/d) or a high (260 kU/kg/d) dose daily for 5 to 7 days. The most frequent adverse effects were transient hepatic transminase elevation and fever. Although some patients noted a transient increase in joint pain, onset of improvement occurred within 7 to 14 days of initiation of DAB486IL-2. Because of these results, a two-center, double-blind, placebo-controlled trial was conducted from December 1991 to December 1992. Forty-five patients with active severe RA unresponsive to at least 2 DMARDS were randomized to placebo or DAB486IL-2 following a 3 to 4 week washout/run-in period to establish a stable baseline (< 40% fluctuation in swollen and painful, tender joint counts).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis and recent onset insulin-dependent diabetes mellitus. 832 45

IL-4 binds to a cell surface receptor complex that consists of the IL-4 binding protein (IL-4R alpha) and the gamma chain of the IL-2 receptor complex (gamma c). The receptors for IL-4 and IL-2 have several features in common; both use the gamma c as a receptor component, and both activate the Janus kinases JAK-1 and JAK-3. In spite of these similarities, IL-4 evokes specific responses, including the tyrosine phosphorylation of 4PS/IRS-2 and the induction of CD23. To determine whether sequences within the cytoplasmic domain of the IL-4R alpha specify these IL-4-specific responses, we transplanted the insulin IL-4 receptor motif (I4R motif) of the huIL-4R alpha to the cytoplasmic domain of a truncated IL-2R beta. In addition, we transplanted a region that contains peptide sequences shown to block Stat6 binding to DNA. We analyzed the ability of cells expressing these IL-2R-IL-4R chimeric constructs to respond to IL-2. We found that IL-4 function could be transplanted to the IL-2 receptor by these regions and that proliferative and differentiative functions can be induced by different receptor sequences.
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PMID:IL-4 function can be transferred to the IL-2 receptor by tyrosine containing sequences found in the IL-4 receptor alpha chain. 862 2

Induction of growth inhibition in human colorectal carcinoma cell lines by interleukin (IL)-4 and IL-13 was associated with the neophosphorylation of a 170 kDa cellular protein, identified as insulin receptor substrate-1 (IRS-1) by immunoprecipitation. Tyrosine phosphorylation of IRS-I was also induced by insulin and insulin-like growth factor I. Sublines of colorectal carcinoma cells unresponsive to growth modulation by IL-4, IL-13 or insulin-like growth factor I-induced growth did not phosphorylate IRS-1. A functional, multimeric IL-4 receptor complex was present on all carcinoma cell lines with a subunit composition of 65 kDa, 75 kDa and the previously characterized 130 kDa band as demonstrated by affinity cross-link with 126I labelled IL-4. The 65 kDa subunit is novel whereas the 75 kDa band represents the common IL-2 receptor gama-chain the novel 65 kDa receptor was present as a double band and bound primarily 125I-labelled IL-13. The present study demonstrates the involvement of a novel chain other than the gama-chain in the receptor complexes of IL-4 and IL-13 and and post-receptor tyrosine phosphorylation of IRS-1. The association of IRS-1 with growth inhibitory signals in carcinoma cells suggests a novel mechanism of tumour growth control.
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PMID:Growth inhibition signalled through the interleukin-4/interleukin-13 receptor complex is associated with tyrosine phosphorylation of insulin receptor substrate-1. 864 56


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