UNIPROT:P14784 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P14784 (IL-2 receptor)
3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 2 (IL-2) and interferon-alpha (IFN-alpha) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase 1B trial of IL-2 plus or minus IFN-alpha in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-alpha and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-alpha and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 x 10(6) units/m2/day or 3.0 x 10(6) units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-alpha (0.5 x 10(6) or 5 x 10(6) units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/IFN-alpha for course 2, or IL-2/IFN-alpha in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-alpha. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-alpha. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-alpha group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum beta 2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-alpha. No dose response effect for IFN-alpha was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-alpha and IL-2.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-alpha in humans. 844 8

Interleukin 2-stimulated human peripheral blood mononuclear cells (PBMC) generate lymphokine-activated killing (LAK). Using the IL-2 analogs R38A and F42K, which interact primarily with the beta and gamma subunits of the IL-2 receptor, we assessed the roles of IL-2R beta gamma and the high-affinity IL-2 receptor complex in LAK activation. Although the kinetics of LAK activation were identical, lytic activity was approximately 30% lower and proliferation was up to 55% lower in those PBMC stimulated by R38A or F42K than in those exposed to wild-type IL-2. The percentage of cells expressing cell-surface markers such as CD3, CD4, CD8, and CD16 was not significantly different after treatment with wild-type IL-2, R38A, or F42K; however, the proportion of cells expressing IL-2R alpha increased dramatically in response to stimulation by F42K (30%) compared to stimulation by either rIL-2 or R38A (15%). In addition, by Day 7 the concentration of soluble IL-2R alpha in analog-stimulated LAK culture supernatants was 50-75% less than that from wild-type IL-2-cultured cells. These findings suggest that interaction of IL-2 with IL-2R beta gamma alone is sufficient for both proliferation and the generation of LAK, and that stimulation with subunit-specific IL-2 analogs results in differential regulation of the IL-2R alpha on human LAK cells.
...
PMID:Characterization of lymphokine-activated killing by human peripheral blood mononuclear cells stimulated with interleukin 2 (IL-2) analogs specific for the intermediate affinity IL-2 receptor. 846 9

Interleukin 2 (IL-2)-deficient (IL-2-/-) mice develop hemolytic anemia and chronic inflammatory bowel disease. Importantly, the induction of disease in IL-2-deficient mice is critically dependent on CD4+ T cells. We have studied the requirements of T cells from IL-2-deficient mice for costimulation with B7 antigens. Stable B7-1 or B7-2 chinese hamster ovary (CHO) cell transfectants could synergize with anti-CD3 monoclonal antibody (mAb) to induce the proliferation of CD4+ T cells from IL-2-/- mutant mice. Further mechanistic studies established that B7-induced activation resulted in surface expression of the alpha chain of the IL-2 receptor. B7-induced proliferation occurred independently of IL-4 and was largely independent of the common gamma chain of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Finally, anti-B7-2 but not anti-B7-1 mAb was able to inhibit the activation of IL-2-/- T cells induced by anti-CD3 mAb in the presence of syngeneic antigen-presenting cells. The results of our experiments indicate that IL-2-/- CD4+ T cells remain responsive to B7 stimulation and raise the possibility that B7 antagonists have a role in the prevention/treatment of inflammatory bowel disease.
...
PMID:Activation of CD4+ T lymphocytes form interleukin 2-deficient mice by costimulatory B7 molecules. 861 Jan 40

Proliferation of T lymphocytes is triggered by the interaction of interleukin 2 (IL-2) with its high affinity specific receptor that is expressed on the cell surface following T lymphocyte activation. Significant advances have recently been made in identifying the multiple signals that follow IL-2 receptor occupancy, although the exact mechanism responsible for IL-2-induced proliferation remains an enigma. It has been shown previously that unique species of phosphatidic acid are rapidly produced in vivo following IL-2 binding. It was then suggested that, in contrast to other eukaryotic growth factor systems, phosphatidic acid was at least in part generated through IL-2-induced diacylglycerol (DG) kinase activation. In the present study we demonstrate IL-2-dependent activation of the alpha isoform of DG kinase. Confocal microscopy studies reveal that the enzyme is located in the cytosol and nuclei of resting T cells. Interleukin 2 stimulation induces translocation of the enzyme to the perinuclear region. Furthermore, our results indicate that inhibition of the alpha isoform of DG kinase has a profound effect on IL-2-induced T cell growth. Studies on cell cycle distribution demonstrate that the inhibition of IL-2-induced phosphatidic acid production induces arrest in late G1 phase of IL-2 dependent cells. Altogether, these results link previous observations of interleukin 2 and phosphatidic acid production to activation of an specific isoform of DG kinase and suggest that activation of this enzyme is part of a novel signaling cascade that utilizes phosphatidic acid as an effector molecule.
...
PMID:Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation. 862 3

Interleukin 2 (IL-2), a T cell-derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the alpha, beta and gamma chains, or the beta and gamma chains. The third component, the gamma chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor, together with the beta chain, the gamma chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same gamma chain as an essential subunit. Interestingly, mutations of the gamma chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the gamma chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the gamma chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the gamma chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.
...
PMID:The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. 871 12

Interleukin 2 (IL-2) mediated signalling results from ligand binding and subsequent heterodimerization of IL-2r beta and gamma c. The high-affinity IL-2 receptor (IL-2r) is a heterotrimer comprised of the IL-2r alpha, IL-2r beta and gamma c subunits. Whereas human IL-2 effectively binds to either human or murine lymphocytes, murine IL-2 binds with markedly higher affinity to murine receptor complexes than to human complexes. Using cell lines stably expressing heterotrimeric IL-2r that vary in the species origin of individual subunits, we have demonstrated that IL-2r alpha is primarily responsible for the species specificity of IL-2 binding. Studies of ligand binding to the low affinity receptor demonstrated that IL-2r alpha displays a similar species preference to the heterotrimeric complex. Moreover, differences in ligand binding are reflected in differences in proliferation. A cell line expressing human IL-2r alpha and IL-2r beta along with murine gamma c vigorously proliferated only in response to human IL-2 at low doses, while both human and murine IL-2 stimulated proliferation of a cell line containing murine IL-2r alpha (as well as human IL-2r beta and murine gamma c). Therefore, IL-2r alpha is the chain primarily responsible for the species specificity of ligand binding.
...
PMID:The alpha chain of the IL-2 receptor determines the species specificity of high-affinity IL-2 binding. 889 36

Interleukin 2 (IL-2) directly affects the function of both neurons and glia in the nervous system. It can induce proliferation and differentiation or cause cell death in oligodendrocytes. We have previously cloned the cDNAs for the alpha (alpha), beta (beta), and gamma (gamma) chains of the IL-2 receptor (IL-2R) complex from a human oligodendroglioma cell line TC620. In an effort to characterize the IL-2 receptor (IL-2R) on oligodendrocytes, experiments were performed using recombinant human IL-2 on normal human oligodendrocytes from adult brain tissue and the IL-2-responsive subclone TC620.6A2 of the oligodendroglioma line. The TC620 subclone has the phenotype of an immature oligodendrocyte. At 5 nM IL-2, there was a 2.5-fold increase in proliferation of both normal and malignant human oligodendrocytes. This response was receptor-mediated in that binding of 125I-IL-2 to TC620.6A2 cells detected a single receptor class for IL-2 with an affinity of 3.6 nM. Immunohistochemical staining of TC620.6A2 cells with a panel of monoclonal antibodies to different epitopes of the human IL-2R alpha chain demonstrated the presence of IL-2R alpha on the surface of these cells, in staining patterns which did not always coincide with those found on T cells. Neither the beta nor the gamma chain of the IL-2R complex was detected on human oligodendrocytes by immunohistochemistry. Those antibodies which recognized cell surface IL-2R alpha epitopes on TC620.6A2 blocked IL-2-induced proliferation, while those which did not detect cell surface IL-2R alpha epitopes were not inhibitory. This same panel of monoclonal antibodies, when used to probe membrane preparations of TC620.6A2 cells on a Western blot, detected three proteins of 100, 83, and 47 kDa, in contrast to the 55-kDa IL-2R alpha observed on T cells.
...
PMID:Response of human oligodendrocytes to interleukin-2. 919 65

Interleukin 2 (IL-2) interacts with a receptor (IL-2R) composed of three subunits (IL-2R alpha, IL-2R beta and IL-2R gamma). IL-2R beta plays a critical role in signal transduction. An anti-human IL-2 mAb (H2-8) produced after immunization with peptide 1-30 of IL-2 was found to recognize the region occupied by Asp20, at the exposed interface between alpha-helices A and C. Muteins at position 17 and 20 are not recognized by mAb H2-8. mAb H2-8 specifically inhibits the IL-2 proliferation of TS1beta cells which are dependent on the expression of human IL-2R beta chain for IL-2 proliferation. Substitution at internal position Leu17 demonstrates that this position is essential for IL-2 binding and IL-2 bioactivity. New IL-2 mutants at position Asp20 have been analysed. Substitutions Asp --> Asn, Asp --> Lys, Asp --> Leu, show a correlation between diminished affinity for IL-2 receptor and reduced bioactivity measured on TS1beta cells. Mutein Asp Arg lose affinity for IL-2R and bioactivity simultaneously. Furthermore, during the course of the study we have found that mutein Asp20 --> Leu is an IL-2 antagonist. The biological effects of mAb H2-8 and the properties of new mutants at positions 17 and 20 demonstrate that this region of alpha helix-A is involved in IL-2-IL-2R beta interactions.
...
PMID:Analysis of human IL-2/IL-2 receptor beta chain interactions: monoclonal antibody H2-8 and new IL-2 mutants define the critical role of alpha helix-A of IL-2. 923 11

The therapeutic value of Interleukin 2 (IL-2) is limited by its short half life and systemic toxicity. One approach to overcoming these problems is to fuse this protein to an antibody, a protein with a long half life and the ability to target a unique antigen within the body. To examine the biochemical properties of such a molecule a fusion protein was constructed linking the N-terminus of human IL-2 to the C-terminus of IgG3. A similar fusion between IgG1 and IL-2 has previously been shown to bind antigen, generate antibody-dependent cellular cytotoxicity (ADCC) and stimulate T cell proliferation and cytotoxicity. We now extend these studies and show that the fusion protein, termed IgG3-IL2, is appropriately N-glycosylated within the IgG3 CH2 domain, binds the human high affinity Fc receptor (Fc gamma RI) with an affinity slightly lower than that of IgG3, and is able to activate complement via the classical pathway to lyse antigen coated sheep red blood cells (SRBC). When used to stimulate the proliferation of the IL-2 dependent cell line CTLL-2, IgG3-IL2 has a specific activity slightly lower than that of human recombinant IL-2 (hrIL-2). In marked contrast, when comparable unit concentrations, as defined by the standard CTLL-2 proliferation assay, are used to stimulate human peripheral blood lymphocytes (PBL), IgG3-IL2 generates significantly greater lymphokine activated killer (LAK) cell cytotoxicity than does hrIL-2. Competition studies show that IgG3-IL2 binds the intermediate affinity form of the IL-2 receptor (IL-2R), consisting of the beta and gamma subunits, with an affinity slightly less than that of hrIL-2. In contrast, IgG3-IL2 shows a greater affinity than hrIL-2 for the high affinity IL-2R, consisting of alpha, beta and gamma subunits. Our studies show that the IgG3-IL2 fusion protein possesses a combination of the biological properties of IgG3 and IL-2 including antigen binding, complement activation, Fc gamma RI binding, IL-2R binding and stimulation of both proliferation and LAK activity. This combination of activities may allow IgG3-IL2 to target humoral and cell-mediated immune activation to the site of an antigen of interest or target an antigen to IL-2R bearing cells or organs.
...
PMID:An IgG3-IL2 fusion protein activates complement, binds Fc gamma RI, generates LAK activity and shows enhanced binding to the high affinity IL-2R. 937 38

Interleukin 2 (IL-2) rapidly induces tyrosine phosphorylation of intracellular substrates, including the IL-2 receptor beta chain (IL-2Rbeta), Janus kinase 1 (Jak1), Jak3, signal transducer/activator of transcription proteins, and Shc, but the mechanism underlying dephosphorylation of these proteins is not known. The src homology 2 (SH2) containing tyrosine phosphatase 1 (SHP-1) is recruited by several hematopoietic surface receptors indicating that this phosphatase plays an important role as a regulator of signaling. We have found that IL-2 induces association of SHP-1 with the IL-2 receptor complex, and that once SHP-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of IL-2Rbeta and the associated tyrosine kinases Jak1 and Jak3. This dephosphorylation is specific as expression of a catalytically inactive form of SHP-1, or expression of the related phosphatase SHP-2 did not result in dephosphorylation of the IL-2 receptor components. Furthermore, we have found that SHP-1 expression is greatly decreased or undetectable in a number of IL-2 independent HTLV-I transformed T cell lines that exhibit constitutive Jak/signal transducer/activator of transcription activation. In HTLV-I infected T cells, down-regulation of SHP-1 expression was also found to correlate with the acquisition of IL-2 independence. These observations suggest that SHP-1 normally functions to antagonize the IL-2 signal transduction pathway and that HTLV-I infection and oncogenic transformation can lead to loss of SHP-1 expression resulting in constitutive activation of IL-2 regulated T cell responses.
...
PMID:Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. 952 Apr 55

<< Previous 1 2 3 4 5 6 Next >>