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)

The inhibitory effects of CsA in cell-mediated immunity are well known. There is controversy about whether CsA directly inhibits the function of accessory cells as well as T lymphocytes. We have used northern blotting to compare the effects of CsA on several human monocyte and T cell mRNAs, and we have performed "CsA-pulsing" experiments to separately evaluate the effect of the drug on accessory and T cells during lymphocyte mitogenesis. CsA blocked the induction of several lymphokine mRNAs in stimulated T cells including IL-2, IFN-gamma, and IL-4. CsF, an analog that is ten times less active than CsA as an immunosuppressant, was some ten times less active in inhibiting lymphokine gene expression in culture. CsA and CsF had little effect on the mRNA for the 55 KD low-affinity IL-2 receptor, but there was decreased expression of the TAC antigen. Exogenous IL-2 reversed the CsA-mediated suppression of cell proliferation and TAC expression. This indicates that the primary block with cyclosporines is at the level of lymphokines rather than lymphokine receptors. CsA did not reduce the levels of several monocyte mRNAs, however. These included c-myc and Il-1 alpha/beta mRNAs, induced by PMA plus Con A, as well as HLA-DR alpha and gamma-Ip10 mRNAs in monocytes treated with IFN-gamma. When monocytes were pulsed with CsA, there was no reduction in their subsequent accessory function for anti-CD3 and lectin responses. T lymphoblasts pulsed with CsA, however, did not proliferate or release growth factor. Likewise in the primary MLR between dendritic cells and T cells, dendritic cells were not impaired following pulsing with CsA, whereas treated T cells made 70% less IL-2. The primary site of action of CsA therefore seems to be the production of lymphokines by T lymphocytes.
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PMID:Evidence that cyclosporine inhibits cell-mediated immunity primarily at the level of the T lymphocyte rather than the accessory cell. 313 67

Initiation of T-lymphocyte proliferation by mitogen or antigen involves a cascade of gene activation events. Thus, by the time mitogen-activated T cells have reached the G1/S interface, many genes that are transcriptionally silent in G0, like the c-myc, IL-2, IL-2 receptor (IL-2R) and transferrin receptor (TfR) genes, have been transcriptionally activated. To understand the role of the individual genes in the activation process, one must be able to interfere specifically with the expression or function of each particular gene product. In this way, by blocking the IL-2R with an antibody, it has been demonstrated that IL-2/IL-2R interaction is required to induce TfR expression in activated T cells. When the function or expression of intracellular proteins is to be blocked, however, the need to introduce antibodies into the cytoplasm of viable cells, although possible, is a limiting factor. We have taken another approach, namely the exogenous addition to bulk cell cultures of small antisense oligomers. Sequence-specific antisense oligodeoxyribonucleotides have been reported to inhibit intracellular viral replication without interfering with cellular protein synthesis. Similarly, rabbit globin mRNA translation in a cell-free system and in rabbit reticulocytes has been inhibited by oligomers complementary to the globin mRNA initiation codon region. Recently, a pentadecadeoxyribonucleotide complementary to the initiation codon and four downstream codons of human c-myc mRNA was reported to inhibit the proliferation of the human leukaemic cell line HL-60 specifically. We report here that the same c-myc complementary oligonucleotide inhibits mitogen-induced c-myc protein expression in human T lymphocytes and prevents S phase entry. Interestingly, c-myc antisense treatment did not inhibit G0 to G1 traversal as assessed by morphologic blast transformation, transcriptional activation of the IL-2R and TfR genes, or induction of 3H-uridine incorporation.
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PMID:A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1. 330 22

We have studied the expression of seven cell cycle-dependent genes in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells, in macrophage-depleted cultures and in macrophage-depleted cultures plus Interleukin-2 (IL-2). The expression of all seven genes is increased in PHA stimulated peripheral cells. Only two (2F1 and the IL-2 receptor) are increased in PHA-stimulated macrophage depleted cultures. Addition of IL-2 to these cultures increased the RNA levels of four genes (KC-1, c-myc, beta-actin and IL-2R), but has no effect on three others (4F1, 2F1, and JE-3). The results indicate that the expression of these cell cycle genes is regulated by different components of the mitogenic stimulus.
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PMID:Effect of interleukin-2 on the expression of cell cycle genes in human T lymphocytes. 387 9

The cellular and molecular regulation of IL-4 mRNA expression in human tonsillar T lymphocytes was examined to define the mechanisms responsible for biphasic IL-4 mRNA expression in this lymphoid organ. Tonsillar T cells expressed IL-4 mRNA in a biphasic manner with peaks at 8 and 24 h after PHA stimulation. De novo protein synthesis was not required for IL-4 mRNA expression because cycloheximide treatment of tonsillar MNC did not ablate the response. Nuclear runoff assays demonstrated transcription of the IL-4 gene at 8 and 24 h, which was not affected by addition of actinomycin D. Separation of T cells into naive (CD45RAhi/CD29lo) and primed (CD45RAlo/CD29hi) subpopulations revealed that although naive and primed T cells expressed IL-4 mRNA at 8 h, the 24-h peak of IL-4 mRNA expression was solely due to primed (CD45RAlo/CD29hi) Th cells. This effect was tissue specific and IL specific in that 1) primed peripheral blood T cells had only one peak of IL-4 mRNA expression at 8 h and 2) in primed tonsillar T cells, mRNA expression of IL-2, IL-6 and IL-2 receptor and c-myc was not delayed. Thus, IL-4 mRNA expression in the tonsil differs depending on the surface expression of different isoforms of the leukocyte common Ag. The tissue- and stimulus-specific regulation of IL-4 mRNA in different lymphoid tissues may play an important role in regional immunoregulation.
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PMID:Tissue-specific regulation of IL-4 mRNA expression in human tonsil. 750 59

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disease of unknown etiology characterized by metaphyseal dysostosis, unpigmented hair, and defective cellular immunity. We studied peripheral blood mononuclear cells (PBMC) of a boy with CHH and combined immunodeficiency in an attempt to characterize further the immune defect in this disease. Stimulation of his PBMC with mitogens was associated with severely depressed IL-2 and interferon-gamma (IFN-gamma) synthesis and IL-2 receptor alpha-chain (IL-2R alpha) expression and resulted in poor lymphocyte proliferation that was only modestly upregulated by the addition of recombinant IL-2 (rIL-2). The defective proliferation and lymphokine synthesis were not corrected by the addition of phorbol myristate acetate (PMA) and ionomycin, agents that bypass receptor-mediated signalling, indicative of a distal abnormality. Importantly, the levels of mRNA encoding c-myc, IL-2R alpha, IL-2 and IFN-gamma were markedly decreased in patient lymphocytes stimulated with PMA+ionomycin as compared to control lymphocytes. The defect in the expression of these early activation genes was selective in that induction by mitogens of mRNA encoding other early activation gene products such as c-fos and c-jun was not impaired. These results suggest that the underlying defect in this patient and perhaps others with CHH may be an abnormality in a component of intracellular signalling pathways or in a trans-acting factor which regulates the expression of a selected number of early activation genes.
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PMID:Defective expression of early activation genes in cartilage-hair hypoplasia (CHH) with severe combined immunodeficiency (SCID). 755 1

A protein-tyrosine phosphatase LC-PTP is preferentially expressed in hematopoietic cells and is an early response gene in lymphokine stimulated cells. Here, we found the LC-PTP mRNA induction by IL-2 was markedly inhibited by several tyrosine kinase inhibitors. The induction required both the acidic and serine-rich regions of the IL-2 receptor beta chain (IL-2R beta) in mouse IL-3-dependent pro-B BAF-B03 transfectants. This is strikingly different from the induction of c-myc gene expression, which requires the serine-rich region alone. In addition, overexpression of activated-Lck or -Raf kinases resulted in augmented LC-PTP mRNA expression in myeloid cell line 32D transfectants. Considering the previous findings that the acidic region of the IL-2R beta is responsible for association with Lck and activation of Raf kinase, IL-2-induced expression of LC-PTP mRNA may be primarily transduced through a Lck-Raf mediated signaling pathway.
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PMID:IL-2-induced gene expression of protein-tyrosine phosphatase LC-PTP requires acidic and serine-rich regions within IL-2 receptor beta chain. 755 30

The IL-2 receptor (IL-2R) consists of three subunits, the IL-2R alpha, IL-2R beta, and IL-2R gamma chains. The IL-2-induced proliferative signals emanate from the cytoplasmic domains of IL-2R beta and IL-2R gamma, but the nature and function of the signaling molecules that transmit these signals are not fully understood. Here, we report that Syk protein tyrosine kinase (PTK) is physically associated with IL-2R in peripheral blood lymphocytes. cDNA expression studies further revealed that this association is critical for the IL-2-induced activation of Syk PTK, which occurs primarily via the serine-rich region of the IL-2R beta chain, which is essential for proliferative signal transmission. Furthermore, we provide evidence that in the hematopoietic cell line, BAF-B03, the activation of Syk PTK results in the induction of the c-myc gene, an event critical for the cell proliferation. Thus, Syk PTK may be a critical integral member of the signaling molecules engaged by the IL-2R.
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PMID:Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway. 760 Mar 4

The addition of recombinant interleukin 2 (rIL-2) to anti-CD3-activated murine G0 phase T cells results in an increased level of tyrosine phosphorylation of a single 97-kDa protein. The degree of tyrosine phosphorylation paralleled the amount of rIL-2 added and correlated with the extent of DNA synthesis. IL-2 treatment resulted in a transient increase in p56lck kinase activity without detectable modification of its level of tyrosine phosphorylation and gel mobility. When G0 T cells were activated by phorbol dibutyrate in the absence of IL-2, the high-affinity IL-2 receptor (IL-2R) expressed failed to induce a proliferative signal, and neither the tyrosine phosphorylation of the 97-kDa protein nor the transient increase in p56lck kinase activity was detected. Northern analysis of the total RNA extracted from these cells showed the accumulation of IL-2R alpha chain-specific mRNA but neither c-myc nor cdc2 mRNA was expressed. The addition of 100 nM rIL-2 to T cells activated by phorbol dibutyrate was able to induce a proliferative response, and under these conditions tyrosine phosphorylation of the 97-kDa protein, the transient increase in p56lck kinase activity, and specific mRNA for IL-2R alpha chain, c-myc, and cdc2 were detected. Unstimulated G0 T cells responded to 100 nM rIL-2 in the same manner as phorbol dibutyrate-activated cells. Irrespective of the signal-transducing structures involved, the IL-2-induced proliferative response closely correlates with an increase in p56lck kinase activity along with the tyrosine phosphorylation of a 97-kDa protein.
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PMID:Murine T-lymphocyte proliferation induced by interleukin 2 correlates with a transient increase in p56lck kinase activity and the tyrosine phosphorylation of a 97-kDa protein. 768 94

We have previously shown that the interleukin 2 (IL-2) receptor gamma chain is a member of the cytokine receptor superfamily and is indispensable for the formation of receptor complexes with high and intermediate affinities for IL-2. The present study demonstrates that the alpha beta gamma heterotrimer and beta gamma heterodimer complexes of IL-2 receptor reconstituted on murine fibroblast L929 cells can transduce IL-2-mediated signals for activation of tyrosine kinase and for induction of c-myc, c-fos, and c-jun expression. A mutant of the gamma chain lacking the C-terminal 68 amino acids in its cytoplasmic region showed a loss of such signal-transducing ability when incorporated into the IL-2 receptor complexes but brought no effect on IL-2 binding and IL-2 internalization. Another mutant, with a C-terminal deletion of 30 amino acids, retained the ability to activate a tyrosine kinase and to induce c-myc expression but lost the ability to induce c-fos and c-jun expression. These results suggest that at least two distinct signals, one for c-myc induction, which parallels tyrosine kinase activation, and the other for c-fos and c-jun induction, can be transduced from the IL-2 receptor complexes reconstituted on fibroblastoid cells.
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PMID:Reconstitution of functional interleukin 2 receptor complexes on fibroblastoid cells: involvement of the cytoplasmic domain of the gamma chain in two distinct signaling pathways. 768 23

Fusion of the YACUT T-cell lymphoma with the Mls-1a-antigen-specific non-tumorigenic T-cell line G4 was previously reported to produce growth-arrested hybrids that could be induced to proliferate in the presence of Mls-1a antigen. The proliferation-suppressed hybrid lines exhibited phenotypic changes as follows: the usually high levels in YACUT of J11d antigen, IL-2 receptor, and c-myb expression, which are markers of immature T cells, were all down-regulated; the G4 T-cell function, i.e., contact helper activity for B-cell proliferation in T/B cell collaboration, was retained. Furthermore, fusion of the YACUT lymphoma with a killer T-cell line produced growth-arrested and tetraploid somatic cell hybrids having killer activity. Thus, in addition to the transformed phenotype (autonomous proliferation in vitro), the antigen-specific non-tumorigenic T-cell line genomes introduced into the YACUT lymphoma suppressed the immature phenotypes of YACUT and imposed their own programming of terminally differentiated traits on the hybrids. Prolonged growth of the proliferation-suppressed hybrid lines by repeated antigenic stimulation was previously reported to result in the appearance of transformed hybrids, which was accompanied by both a reversion of c-myc expression to the levels of YACUT and an increase in the number of chromosome 15. The present study revealed that the amplification of chromosome 15 resulted from the duplication of the tumour-derived chromosome 15 carrying the rearranged pvt-1 gene. However, the differentiated phenotypes of the hybrids remained mostly unchanged upon cell transformation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of duplication of tumour-derived chromosome 15 carrying the rearranged pvt-1 gene in the transformed phenotype of YACUT T-cell lymphoma x G4 T-cell line somatic cell hybrids in dictating the terminal differentiation program of the parental G4 cell. 787 44


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