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

Measles virus (MV) inhibits lymphocyte function in patients, as well as in cells infected in vitro. The proliferation of phytohemagglutinin-stimulated T lymphocytes is suppressed by in vitro MV infection, as shown by the diminished incorporation of [3H]thymidine into DNA and the reduced frequency of cells in the S phase of the cell cycle, as compared with mock-infected cells. MV infection itself, however, does not completely block DNA synthesis in infected cells, because infected T cells expressing MV antigens on the cell surface, isolated by fluorescence-activated cell sorter, could still proliferate. Northern blot analysis indicated that the expression of genes induced during T cell activation, such as those encoding interleukin 2 (IL-2), c-myc, IL-2 receptor, IL-6, c-myb, and cdc-2, was not significantly suppressed in MV-infected cells, suggesting that MV does not interfere with the T cell activation process. When anti-MV serum or carbobenzoxy-D-Phe-L-Phe-Gly, a synthetic oligopeptide known to inhibit MV-induced fusion, was added 24 hr after infection, the inhibition of T cell proliferation was reversed in a dose-dependent manner. From these results we propose a model for the inhibition of T cell proliferation by MV; MV glycoproteins expressed on the cell surface of infected cells interact with the MV receptor or other molecules on the cell membrane of adjacent T cells, which in turn affects the proliferation of those T cells.
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PMID:Measles virus inhibits mitogen-induced T cell proliferation but does not directly perturb the T cell activation process inside the cell. 173 30

The immunosuppressive drug, mizoribine, has been used to prevent rejection of organ allografts in humans and in animal models. Based on studies in cell lines, mizoribine has been postulated to be an inhibitor of inosine monophosphate (IMP) dehydrogenase (EC1.2.1.14), a pivotal enzyme in the formation of guanine ribonucleotides from IMP. To further characterize the mechanism of action of this drug, we studied the effect of mizoribine on human peripheral blood T cells stimulated with alloantigen, anti-CD3 MAb, or pharmacologic mitogens. Mizoribine (1-50 micrograms/ml) was able to inhibit T cell proliferation by 10-100% in a dose-dependent fashion to all stimuli tested. Measurements of purine ribonucleotide pools by HPLC showed that mizoribine led to a decrease in intracellular GTP levels, and that repletion of GTP reversed its antiproliferative effects. We also examined sequential events occurring after T cell stimulation. Early events in T cell activation, as assessed by steady-state mRNA levels of c-myc, IL-2, c-myb, histone, and cdc2 kinase, as well as surface IL-2 receptor expression, were unaffected. However, cell cycle analysis revealed decreased numbers of cells in S, G2, and M phases, and showed that the G1/S block was reversed with GTP repletion. These data indicate that mizoribine has an effect on T cell proliferation by a mechanism distinct from that of cyclosporine or corticosteroids, and therefore may be useful in combination immunosuppressive regimens.
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PMID:Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine. 199 2

It is well-known that the most prominent age-related immunological abnormalities were reduced immune response against foreign antigens and increased auto-antibody production against intrinsic antigens. To explain these immunological abnormalities, we examined the various functions of human lymphocytes from aged and young groups at cellular, molecular and genetic levels. The results indicate: The first, T cells from the aged showed significantly reduced proliferative response not only to specific antigen TAP but also to mitogen PHA or combined stimulation of PMA and ionomycin. The second, the number of IL-2 receptor, particularly high affinity ones, on aged T cells were significantly reduced in the aged after TAP and PHA stimulation. The third, the ability to express Tac (p55) and p70/75 of IL-2R and to internalize the rIL-2 bound to the receptor were reduced in aged T cells. The fourth, although the ability to proliferate in response to SAC stimulation was two folds less in the aged B cells than that in the young ones, the capacity to differentiate into IgG and IgA class ISC after the combined stimulation with SAC and partially purified BCDF were rather increased on the basis of the number of viable cells recovered. The fifth, the amount of IL-2 activity produced by aged T cells was ten fold less than that by young ones, but the amount of BCDF activity produced by aged T cells was three folds higher than that by young ones after PHA stimulation. An inverse correlation between IL-2 activity and BCDF activity was found when the both activities were determined in the same sample. The sixth, the combined stimulation with PMA and ionomycin could induce proliferative response to highly purified T cells, T cell subsets and B cells. The degree of age-related decline of the proliferative response of CD-8 positive T cells was most significant, that of CD-4 positive ones was next and that of B cells was least. The seventh, although the maximum of c-myc mRNA level was attained at 2 hr after the stimulation and similar amount between the both age groups, the amount of mRNA at 8 or 24 hr was rather higher in the aged T cells than in the young ones. The reduction of the degradation rate of c-myc mRNA seemed to be the cause. We found no difference of the maximum amount and kinetics of c-myb mRNA between both age groups in T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The characteristic changes of immune function with aging]. 281 Oct 4

The relationship between induction of nuclear proto-oncogenes and cellular proliferation is not fully understood. To better define this relationship, we have studied c-fos, c-myc, and c-myb mRNA induction in T lymphocytes where early and late activation events have been clearly delineated. In T cells, initial activation from G0 to G1 results from stimulation of either the antigen/major histocompatibility complex receptor (T3-Ti) or the T11 structure; further cycle progression and proliferation follow interaction of interleukin 2 (IL-2) with the IL-2 receptor. These events can be dissected with monoclonal antibodies to T3 or T11 which cause early activation but differ in their ability to initiate IL-2-dependent cycle progression and proliferation. In T lymphocytes triggered through either T3-Ti or T11, c-fos is induced with a nonmitogenic activation signal whereas c-myb is only induced with a mitogenic signal capable of triggering IL-2 and IL-2 receptor expression. Furthermore, c-myc induction is biphasic and associated with both early and late activation events. Early c-myc, like c-fos, is induced with a nonmitogenic signal. In contrast, induction of late c-myc, like that of c-myb, requires a mitogenic signal. Thus, appearance of c-fos and initial c-myc mRNA seem to be early responses to membrane signaling whereas late c-myc and c-myb are more directly associated with actual cellular proliferation. That nonmitogenic stimulation of T cells via T3-Ti not only abrogates T11-mediated proliferation but also eliminates late c-myc and c-myb transcription further supports this notion.
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PMID:Differential expression of nuclear proto-oncogenes in T cells triggered with mitogenic and nonmitogenic T3 and T11 activation signals. 282 Nov 8

A novel IL-2 receptor, distinct from the Tac protein, has been identified on the surface of purified human natural killer (NK) cells by chemical cross-linking of 125I-IL-2. This protein is approximately 70,000 D in size (p70) and appears to be identical to the recently recognized second subunit of the human high affinity IL-2 receptor complex. Scatchard analysis of 125I-IL-2 binding to purified NK cells revealed approximately 2,300 p70 binding sites per cell with an apparent dissociation constant of 200 pM, a value intermediate between the previously recognized high and low affinity forms of the human IL-2 receptor. The monoclonal anti-Tac antibody did not inhibit the cross-linking of 125I-IL-2 to the p70 binding sites present on NK cells. Functionally, the addition of high concentrations of recombinant IL-2 to the enriched NK cells promoted a rapid augmentation of cytolytic activity and a more delayed increase in cellular proliferation. Anti-Tac effectively blocked the IL-2-induced proliferative response in these cells, but failed to alter the enhancement of cytotoxicity. Analysis of NK cytoplasmic RNA isolated at various time points after IL-2 stimulation revealed the rapid induction of c-myb and Tac gene expression that was also not inhibited by the anti-Tac antibody. These findings suggest that IL-2 binding to the p70 receptor constitutively expressed on the surface of NK cells may mediate both the development of increased cytolytic activity and rapid changes in gene expression. The activation of the Tac gene may in turn permit the formation of the high affinity IL-2 receptor complex (comprised of at least the Tac and p70 proteins) that appears to transduce the requisite signals involved in NK cell proliferation.
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PMID:Novel interleukin 2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells. 282 41

Elevation of intracellular cyclic adenosine 3':5' monophosphate (cAMP) inhibits interleukin 2 (IL-2)-stimulated proliferation of a murine cytotoxic cell clone, CT6. The effects of antiproliferative dosages of stable cAMP-derivative, 8-bromoadenosine 3':5'-monophosphate (8-Br-cAMP), on steady state mRNA expression stimulated by IL-2 was examined. IL-2 stimulated mRNA accumulation of three nuclear proto-oncogenes c-fos, c-myc, and c-myb. 8-Br-cAMP alone stimulated c-fos, c-myb, and IL-2 receptor mRNA accumulation as determined by Northern blot analysis. 8-Br-cAMP, however, markedly inhibited c-myc expression stimulated by IL-2. Furthermore, although c-fos and IL-2 receptor mRNA expression was potentiated by 8-Br-cAMP, suppression of protein synthesis was seen. We show that antiproliferative cAMP stimulates similar mRNA expression as does IL-2, with the exception of c-myc. Although a comparative stimulation of steady state mRNA accumulation of some genes occurs, cAMP may profoundly effect protein synthesis. cAMP, therefore, acts on multiple targets involved in the macromolecular events stimulated by IL-2.
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PMID:Effects of anti-proliferative cyclic AMP on interleukin 2-stimulated gene expression. 304 Aug 63

This review covers significant developments in the understanding of the biochemistry and clinical pharmacology of Interleukin-2 (IL-2) that were achieved from 1984 through September 1986. These include developments in the molecular biology of IL-2 and its receptors. Human IL-2 was cloned and sequenced by Taniguchi et al. in 1983. The gene for human IL-2 is located on the long arm of chromosome 4. The secondary structure of the gene is predominantly alpha helix. The mature gene product is a 133 amino acid glycoprotein with a molecular weight of 15,420 Daltons. The IL-2 receptor was revealed to be a glycoprotein of 272 amino acids. The mature receptor has a molecular weight of 55,000 Daltons. A more precise understanding of the mechanism of action IL-2, in particular its role in the induction of the IL-2 receptor, and aspects of the control of IL-2 production was also achieved. Metabolic and morphologic studies have revealed that activation of the T-cell antigen receptor renders the cells responsive to IL-2, but does not move them through the cell cycle. Rather, it appears that IL-2 stimulates G1 progression to S phase ie. blastic transformation. During this progression the cellular proto-oncogene c-myb is induced transiently to 6 to 7 times basal levels. The role of IL-2 as a growth factor for several subsets of T cells has been confirmed, and a new role as a growth factor for B cells was defined. Most importantly, IL-2 was shown to be directly mitogenic for and to expand subpopulations of peripheral blood cells, termed lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL). A number of pathologies of IL-2 production or activity have been defined, including Hodgkin's disease, graft versus host disease, systemic lupus erythematosus, lepromatous leprosy, acquired immune deficiency syndrome, and adult T cell leukemia. Murine and human in vivo studies reviewed here have revealed significant parameters of the therapeutic potential as well as the toxicity of this growth factor. Finally, the modulation of IL-2 receptors on human PBL's by thymosin fraction 5 and thymosin alpha 1 suggests that it might be possible to up-regulate IL-2 receptor expression in certain disease states and thus increase the efficacy of IL-2.
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PMID:Recent advances in the understanding of the biochemistry and clinical pharmacology of interleukin-2. 354 63

Human immunodeficiency virus type 1 (HIV-1) Nef protein causes the loss of cell surface CD4 and interleukin-2 (IL-2) receptor (Tac) from peripheral blood mononuclear cells (PBMC) and CD4+ T-cell lines. As both CD4 and the IL-2 receptor play crucial roles in antigen-driven helper T-cell signalling and T-cell proliferation, respectively, the role of Nef in the viral life cycle may be to perturb signalling pathways emanating from these receptors. However, the intracellular targets for Nef that result in receptor down-regulation are unknown. Using a recombinant glutathione S-transferase-full-length 27 kDa Nef (Nef27) fusion protein, produced in Escherichia coli by translation from the first start codon of HIV-1 nef clone pNL4-3, as an affinity reagent to probe cytoplasmic extracts of MT-2 cells and PBMC, we have shown interaction with at least seven host cell protein species ranging from 24 to 75 kDa. Immunoblotting identified four of these proteins as p56lck, CD4, p53, and p44mapk/erk1, all of which are intimately involved in intracellular signalling. To assess the relevance of these interactions and further define the biochemical activity of Nef in signal transduction pathways, highly purified Nef27 protein was introduced directly into PBMC by electroporation. Nef27-treated PBMC showed reduced proliferative responsiveness to exogenous recombinant IL-2. Normally, stimulation of T-cells by IL-2 or phorbol 12-myristate 13-acetate provokes both augmentation of p56lck activity and corresponding posttranslational modification of p56lck. These changes were also inhibited by treatment of PBMC with Nef, suggesting that Nef interferes with activation of p56lck and as a consequence of signalling via the IL-2 receptor. Further evidence for Nef interfering with cell proliferation was the decreased production of the proto-oncogene c-myb, which is required for cell cycle progression, in Nef-treated MT-2 cells. In contrast to the binding characteristics and biological effects of Nef27, the alternate 25-kDa isoform of Nef (Nef25) produced by translation from the second start codon of HIV nef pNL4-3 (57 nucleotide residues downstream) was shown to interact with only three cellular proteins of approximately 26, 28, and 56 kDa from PBMC and MT-2 cells, one of which was identified as p56lck. Also, proliferation and posttranslational modification of p56lck in response to IL-2 stimulation were not profoundly affected by treatment of PBMC with Nef25 compared with Nef27.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. 785 25

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

The expression of various proto-oncogenes in primary culture of lymphocytes from peripheral blood of bovine with chronic lymphocytic leukemia (CLL) was studied. Cellular proto-oncogenes encode proteins that propagate growth, differentiation or apoptosis signals from cell membrane to nucleus. The proliferation and differentiation of normal eukaryotic cells are precisely controlled. Tumor cells usually are characterized both by the continuous growth signal and by the block of cell differentiation. We have previously reported that along with spontaneous proliferation, bovine CLL lymphocytes continuously differentiate and enter apoptosis in vitro. CLL cells with an autocrine growth mechanism and at the same time undergoing spontaneous differentiation and apoptosis in vitro provide a new model system to investigate the possible involvement of various proto-oncogenes in the regulation of cellular proliferation, differentiation and apoptosis. Northern blot analysis revealed simultaneous expression of a number of proto-oncogenes in CLL cells. Transcripts of c-fos, c-myc, c-myb, A-raf, c-raf1, hck, IL-2 receptor alpha-chain (IL-2R alpha) were found in lymphocytes at the peak of their proliferative activity in culture. Kinetics studies demonstrated that CLL cells constitutively express transcripts of so-called immediate response nuclear proto-oncogenes c-myc, c-fos as well as cytoplasmic proto-oncogenes hck and c-raf1, i.e., genes coding for tyrosine and serine-threonine protein kinases, respectively. Expression level did not change significantly during all stages of CLL cells in culture. The results show that continuous expression of c-myc mRNA does not prevent CLL cell differentiation and may be associated with apoptotic cell death.
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PMID:Proto-oncogene expression in bovine peripheral blood leukemic lymphocytes during their spontaneous proliferation, differentiation and apoptosis in vitro. 959 70


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