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)

It is known that interleukin-2 (IL-2) plays an important role in the activation of host antitumor immune response. In addition to IL-2 cell surface receptor, a soluble form of IL-2 receptor (SIL-2R) may be released in the blood and potentially be involved in the regulation of IL-2 availability. High SIL-2R levels have been found in patients with lung cancer. The current study evaluated the influence of changes in SIL-2R serum levels during the perioperative period on early relapse rate in patients with operable non-small cell lung cancer. The study included 60 patients (epidermoid carcinoma, 33; adenocarcinoma, 27). Serum levels of SIL-2R were measured with an enzyme immunoassay before surgery and 7 and 30 days after surgery. A surgery-induced increase in SIL-2R levels was seen 7 days after surgery in 38 of 60 patients. On the 30th day after surgery, SIL-2R values were lower than the preoperative values in 32 patients (Group A) or still greater in the other 28 patients (Group B). After a median follow-up of 10 months, relapse occurred in 19 of 60 patients. The relapse rate was significantly higher in Group B than in Group A patients (16 of 28 versus 3 of 32, respectively; P less than 0.001). This difference also was significant in relation to histotype and node status. This study shows that the persistence of increased SIL-2R levels in the postoperative period is associated with a higher early relapse rate in patients with operable non-small cell lung cancer. The impact of SIL-2R levels on relapse suggests that host immune defenses may influence the clinical course of patients with lung cancer. Therefore, the evaluation of SIL-2R in the perioperative period may represent a new prognostic biologic factor in operable non-small cell lung cancer.
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PMID:Postoperative increase in soluble interleukin-2 receptor serum levels as predictor for early recurrence in non-small cell lung carcinoma. 131 91

Cytokines, a class of soluble mediators involved in cell-to-cell communication, are generated in response to many stimuli by a variety of tissues. They include interferons (IFNs), Interleukins (ILs) and colony stimulation factors (CSFs), and have been most extensively studied in the context of hematopoiesis and immune responses, however their molecular nature remained totally elusive due to the scarcity of the cytokines produced, under optimized conditions for producer cells. With the advent of recombinant DNA technology, we have isolated in 1983 the gene encoding one of the first identified Interleukins, IL-2, and thus initiated our molecular analyses of the IL-2 system. In fact, IL-2 plays a major role in the clonal expansion of T lymphocytes (T cells) by interacting with specific cell surface receptor (IL-2 receptor). The functional, high-affinity form of IL-2 receptor (IL-2R) is composed of two receptor components, IL-2R alpha (p55) and IL-2R beta (p70-75) chains. We have cloned a human and murine IL-2R beta cDNAs. Unlike the IL-2R alpha chain, the IL-2R beta chain contains a large cytoplasmic domain which shows no obvious tyrosine kinase motif. We established a system in which the cDNA-directed human IL-2R beta allows growth signal transduction in murine IL-3-dependent cell lines. Utilizing this system, we have identified a cytoplasmic region of the receptor critical for the growth signal transduction. Furthermore, we have provided evidence for the physical association of IL-2R beta with protein tyrosine kinase, 56lck. The functional significance of such association may be profound in understanding the general mechanisms of cytokine-induced signal transduction.
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PMID:Structure and function of IL-2 and IL-2 receptors. 152 74

Surgically induced immunosuppression may play a role in cancer, because of the possible existence of micrometastases at the time of surgical removal of tumors. Antitumor immune reactions are mediated by interleukin-2 (IL-2). IL-2 acts on a specific IL-2 cell surface receptor; moreover, a soluble form of IL-2 receptor (sIL-2R) can be released in the blood. This study was carried out to evaluate the effect of surgery on sIL-2R serum levels in patients with operable solid tumors. A total of 48 patients with cancer and 11 controls who underwent major surgery for non-neoplastic disease were evaluated before and 7 days after surgery. Serum mean levels of sIL-2R were significantly higher after than before surgery in both the cancer and control groups. No correlation was seen between surgery-induced changes in sIL-2R and in T lymphocyte subsets. Because of its capacity of binding to IL-2, the increased blood concentrations of sIL-2R could reduce the IL-2 availability and negatively affect antitumor immune reactions.
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PMID:Effect of antitumor surgery on soluble interleukin-2 receptor serum levels. 182 61

Both immunostimulatory and immunosuppressive events would occur during the immunotherapies of cancer, including interleukin 2 (IL-2) therapy. The marked increase in soluble IL-2 receptor (SIL-2R) levels during IL-2 therapy could represent a potentially negative biological effect, because of the receptor's capacity to bind IL-2 and compete for it with IL-2 cell surface receptor. Since it has been observed that macrophages stimulate in vitro the release of SIL-2R, a study was started to evaluate in vivo the role of macrophages in IL-2-induced SIL-2R rise by measuring neopterin, which is a marker of macrophage activity. The study included 9 advanced renal cancer patients, treated subcutaneously with IL-2 at 1.8 x 10(6) IU/m2 twice daily for 5 days/week for 6 weeks. Both SIL-2R and neopterin serum mean levels significantly increased during IL-2 treatment, and the highest concentrations were reached on the second week of therapy. SIL-2R rise was significantly correlated to that of neopterin. This study, by showing a positive correlation between SIL-2R and neopterin rise, would suggest a macrophage involvement in the stimulation of SIL-2R release during IL-2 immunotherapy of cancer.
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PMID:Increase in soluble interleukin-2 receptor and neopterin serum levels during immunotherapy of cancer with interleukin-2. 183 85

In a phase I/II dose escalation study performed at our institution, a total of 14 advanced metastatic cancer patients received between 4 and 16 weeks of subcutaneous recombinant interleukin-2. Doses were escalated at weekly intervals, starting at 1.8 million IU/m2/day up to a maximum dose of 14.4 million U/m2 daily. When comparing patients with (n = 4) and without (n = 7) prior chemotherapy on day 0 (i.e., before rIL-2), both patient groups exhibited Tac IL-2 receptor (CD25) positive peripheral blood lymphocytes at equal levels of positivity (8%). In contrast, 4-week systemic treatment with subcutaneous rIL-2 at escalating dose levels revealed a significant difference in the up-regulation by interleukin-2 of CD25 cell surface receptor. Thus, after 4 consecutive weeks of treatment, patients without previous chemotherapy showed a mean CD25 positivity of peripheral blood lymphocytes at 38%, as compared with 22% in patients who did receive prior chemotherapy (p less than 0.05). These data suggest that chemotherapy pretreatment may have a significant effect on biological response to rIL-2 in vivo.
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PMID:Diminished expression of interleukin-2 receptors in vivo after prior chemotherapy in advanced cancer patients receiving recombinant interleukin-2. 191 Jun 21

Interleukin 2(IL-2), a lymphokine that is produced by helper T cells, plays a key role in the proliferation of T lymphocytes by interacting with a specific cell surface receptor. Recent studies demonstrated that the IL-2 receptor exists in two forms having different affinities to the ligand and the growth signal seems to be delivered by IL-2 bound to the high affinity, but not the low affinity, receptor. In man, both forms of the IL-2 receptor can be recognized by a monoclonal antibody, anti-Tac. Using this antibody, a cDNA that encodes Tac antigen has been cloned from ATL-derived T cell line. Transfection of the cloned cDNA into mammalian non-T cells, however, resulted in the expression of only a non-functional, low affinity IL-2 receptor. This observation raised a question whether or not the cloned cDNA for Tac antigen actually encodes the functional, high affinity IL-2 receptor. In order to clarify this problem, Tac antigen cDNA was obtained from human PBL cDNA library. This cDNA was connected to RSV-LTR and was transfected into mouse thymoma derived T-cell line EL4, and L929 fibroblast. Then transformants that constitutively express Tac antigen were established. IL-2 binding assay demonstrated that EL4 transformants expressed high affinity as well as low affinity human IL-2 receptor. In contrast, L929 transformants expressed only a low affinity receptor. The growth of the EL4 transformants harboring the high affinity human IL-2 receptor was inhibited by virtue of the specific interaction of the receptor with human, but not mouse, recombinant IL-2. These results demonstrate: the cloned cDNA dose encode a functional IL-2 receptor, the affinity of the IL-2 receptor is variably modified by post-translational events and 3. IL-2/receptor interaction leads to the reversal of the cell growth in EL4 cells. The reconstitution system described here will be of great use in elucidating the mechanism of T cell growth.
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PMID:[Expression of functional human interleukin 2 receptor in mouse cells by using gene transfection]. 309 55

Interleukin 2 provides a signal for the proliferation and differentiation of several classes of immune cells, including activated T cells, natural killer cells and certain activated B cells. The responses to this lymphokine result from its interaction with a high-affinity cell surface receptor. Several structural features of the IL-2 molecule are essential for its functional integrity. For example, an intramolecular disulfide bridge connecting cysteine residues in positions 58 and 105 maintains an active conformation of the molecule. In addition, antibodies directed against epitopes defined by amino acids 8-27 and 33-54 are capable of directly blocking the physiological response. Amino acids in or near these regions may form part of the receptor binding site of IL-2. The receptor for IL-2 exists in both high and low-affinity states. Physiological responses correlate with binding to the high-affinity form of the receptor as determined by anti-IL-2 antibody competition curves. Expression of the cDNA corresponding to the receptor protein in mouse L cells, however, indicates that this protein alone is incapable of high-affinity interaction with IL-2. Thus, the high-affinity conformation of the receptor may entail the interaction of the ligand-binding component with an additional receptor subunit(s). The availability of pure ligand and receptor as well as antibody reagents to both these components make the IL-2 receptor system an ideal model for dissecting an immune response at the molecular level.
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PMID:Interleukin 2 and its cell-surface receptor. 393 74

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

A unique immunoliposome has been developed as a drug delivery vehicle for immunotherapy. Human recombinant interleukin-2 (IL-2) has been chemically coupled to the external surface of small unilamellar vesicles (SUVs) containing methotrexate as a candidate immunosuppresive agent in order to specifically direct the drug-bearing liposome to activated T-cells expressing the high affinity IL-2 receptor. This drug delivery system is designed to deliver an immunosuppressive agent to those cells that actively participate in disorders such as graft rejection without delivering an effective but potentially toxic drug to all cells of the immune system as well as other healthy tissues. IL-2 was chemically modified with succinimidyl 4-[p-maleidophenyl butyrate](SMPB) while the receptor binding domain on IL-2 was protected by monoclonal anti-IL-2 bound to Protein A-Silica Gel. The antibody recognizes the receptor binding domain of the IL-2 molecule. The IL-2 was derivatized with S-succinimidyl-S-thioacetate (SATA) in order to add an acetyl thioester group to the lipid and create the complex. The derivatized lipid (SATA-PE) was then part of the liposome formulation containing DSPC:cholesterol: SATA-PE at a mole ratio of 1.5:1.0:0.26. SMPB-IL-2 was covalently coupled to the external surface of the SUV after deacetylation of the thioester moiety at pH 7.4 in PBS. Liposomes prepared by sonication or extrusion had an average diameter of 46-50 nm. SUV-IL-2 bound to the high affinity IL-2 receptor as measured by competitive binding assays and Scatchard analysis using 111InCl2-loaded liposomes The preparation exhibited a binding constant of 30 pM, consistent with values for free IL-2 cited in the literature. SUV IL-2 could be used as the sole source of IL-2 for the murine CTLL-2 T-cell line or for human mitogen-activated PBLs. The presence of IL-2 coupled to the surface was absolutely required for delivery of the drug to the cell. When methotrexate was encapsulated within the internal aqueous space, receptor-mediated endocytosis led to the inhibition of proliferation due to delivery of MTX to the cytoplasm of the cell. More than 90% of the methotrexate was retained within the liposome during storage over a 24-h period at 4 degrees C. This immunoliposome represents a new class of cell specific immunoliposomes whose entry into the cell is controlled by a cell surface receptor.
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PMID:The development of IL-2 conjugated liposomes for therapeutic purposes. 954 72

An interleukin-2 (IL-2) variant containing adjacent point mutations (L18M/L19S, termed 2D1) displaying binding affinity to the heterotrimeric IL-2 receptor similar to that of wild-type IL-2 (WT) had been previously found to surprisingly exhibit increased bioactivity in a peripheral blood lymphocyte proliferation assay. In order to provide an explanatory mechanism for this unexpected potency enhancement, we hypothesize that altered endocytic trafficking of the 2D1 variant might be responsible by increasing the number of ligand-receptor complexes. We demonstrate here that the internalization kinetics of 2D1 via the high affinity IL-2 receptor are equivalent to those of WT but that a significantly increased fraction of internalized 2D1 is sorted to recycling instead of to lysosomal degradation. We further find a reduced pH sensitivity of binding to IL-2 receptor alpha relative to IL-2 receptor beta compared with WT, which could be responsible for the altered sorting behavior of 2D1 in the acidic endosomal compartment. Accordingly, the 2D1 variant displays a half-life 36 h longer than that of IL-2 in T-lymphocyte culture at concentrations equal to the K(D) of the IL-2 receptor. The extended half-life of intact 2D1 provides enhanced mitogenesis as compared with IL-2. In addition, 2D1 stimulates natural killer cells to a lesser degree than IL-2 at equal concentrations. We conclude that this IL-2 variant provides increased mitogenic stimulation that could not be easily predicted from its cell surface receptor binding affinity while minimizing undesired stimulation of natural killer cells. This concept of altering trafficking dynamics may offer a generalizable approach to generating improvements in the pharmacological efficacy of therapeutic cytokines.
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PMID:Increased endosomal sorting of ligand to recycling enhances potency of an interleukin-2 analog. 1070 36


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