Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00082 (IL-2)
 29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD28 is a glycoprotein expressed as a homodimer on the surface of a major subset of human T cells. Previous studies have shown that proliferation of peripheral blood T cells involving the CD28 pathway is associated with cyclosporine A (CsA) resistant IL-2 gene expression. This pathway was shown to specifically regulate the stability of mRNA for several lymphokines including IL-2. We have investigated the expression of the IL-2 gene in the Jurkat cell line, J32 clone, induced by CD28 stimulation. Cross-linked anti-CD28 mAb alone was sufficient to induce the release of small amounts of IL-2 (256 U/ml). The CD28-mediated IL-2 release was enhanced with simultaneous engagement of CD28 and CD2 or CD28 and CD3 molecules. Hybrid constructs in which the human IL-2 gene 5' flanking region drives luciferase expression (pIL-2-Luc) were used to help delineate whether the CD28 pathway activates the IL-2 gene transcriptionally. Costimulation of cells with CD28 mAb and either PHA or CD2 mAb induced a 20- to 90-fold increase in the expression of pIL-2-Luc as well as IL-2 release. Costimulation with CD28 mAb plus PMA gave only five- to sevenfold increase in enhancer activity. In contrast, no enhancer activity was detected after stimulation with CD28 or CD2 mAb alone. Both IL-2 release and pIL-2-Luc activity were inhibited by CsA in J32 cells. The degree of CsA inhibition was concentration dependent and was similar in cells stimulated with either CD28 mAb or CD3 mAb. Maximum inhibition was achieved with 1 microgram/ml of CsA. Studies with internal deletion mutations of the IL-2 gene 5' flanking sequence revealed that as with stimulation through the TCR pathway, the CD28 pathway requires 5' flanking sequences located within 500 bp of the transcription start site. These results are the first direct evidence that the triggering of CD28 molecule is sufficient to induce IL-2 release in J32 cells. Furthermore these studies strongly indicate that IL-2 gene expression induced by CD28 stimulation occurs, in part, transcriptionally and is CsA sensitive in these cells.
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PMID:CD28-stimulated IL-2 gene expression in Jurkat T cells occurs in part transcriptionally and is cyclosporine-A sensitive. 134 20

The third component of the interleukin (IL) 2 receptor, gamma chain, is essential not only for IL-2- but also for IL-4-, IL-7-, IL-9-, and IL-15-induced proliferation of lymphocytes. To elucidate the mechanisms by which the gamma chain is expressed, we have analyzed the promoter region of the gamma chain gene. The 633-base pair fragment upstream of the initiation codon showed the promoter activity in human hematopoietic cell lines, Jurkat and THP-1, when linked to the luciferase gene. With a series of 5'-deletion mutants, the basal promoter activity was found in a fragment from nucleotide 80 to 58 upstream from the RNA start site, including an Ets binding sequence. Treatment of cells with either 12-O-tetradecanoylphorbol-13-acetate or phytohemagglutinin but not forskolin induced transcription from the gamma chain gene promoter. A viral trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I elevated expression of the gamma chain gene. In contrast, IL-2 decreased transcription from the IL-2 receptor gamma chain promoter. These results suggest that expression of the gamma chain is regulated at the transcription level by extracellular stimuli and may be implicated in immune response.
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PMID:Functional analysis of the human interleukin 2 receptor gamma chain gene promoter. 770 94

The proliferation of activated T lymphocytes is critically dependent on the binding of the T-cell growth factors, interleukin (IL)-2 and IL-4, to distinct but evolutionarily related cell surface receptors. Previous results suggest that the IL-2 receptor (IL-2R) and IL-4R are coupled to both overlapping and distinct intracellular signaling pathways in T lymphocytes. In this study, we demonstrate that activation of Janus tyrosine kinases (JAKs) and STAT transcription factors is rapidly induced by exposure of factor-dependent murine T-cell lines to IL-2 or IL-4. Both IL-2 and IL-4 stimulated the rapid activation of JAK1 and JAK3, whereas JAK2 activity was unaffected by either cytokine. These responses were accompanied by the appearance in cell nuclei of 3 DNA binding activities that recognized a high-affinity binding site for STAT factors. In transient transfection assays, this STAT factor target sequence conferred IL-2 and IL-4 inducibility on a synthetic luciferase reporter gene. Antibody supershifting experiments indicated that IL-2 induces the formation of STAT dimers containing STAT3 and STAT1 alpha. Although IL-4 also activated STAT1 alpha, the major IL4-induced STAT factor is not STAT3 and remains undefined. Pretreatment of the T-cells with the protein-tyrosine kinase inhibitor herbimycin A blocked both the nuclear translocation of STAT factors and STAT-dependent reporter gene transcription. Immunoblot analyses confirmed that cytoplasmic STAT3 was heavily phosphorylated on tyrosine in IL-2-stimulated cells, and that phosphorylated STAT3 appeared in the nuclei of these cells. These results indicate that identical JAKs and partially overlapping sets of STATs are activated by IL-2 and IL-4 in T lymphocytes.
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PMID:Protein-tyrosine kinase-dependent activation of STAT transcription factors in interleukin-2- or interleukin-4-stimulated T lymphocytes. 774 3

We show here that ligation of surface immunoglobulin or CD40 receptors in conjunction with interleukin-4 induces the nuclear factor of activated T cells (NF-AT) in normal murine B cells, which is inhibited by cyclosporin (CsA). Lipopolysaccharide, which activates B cells by a Ca(2+)-independent, CsA-resistant pathway, does not induce NF-AT. The NF-AT complex in T cells and B cells appears to be identical, comprising both Fos and Jun proteins and the 120 kDa cytosolic component of NF-AT (NF-ATp). Our transfection experiments using a trimerized NF-AT site linked to the minimal IL-2 promoter driving luciferase activity demonstrate that NF-AT is functional in A20 B-lymphoma cells. These results therefore suggest that the induction of NF-AT forms part of the B cell response to both cross-linking antigens and T cell-generated signals.
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PMID:Induction of NF-AT in normal B lymphocytes by anti-immunoglobulin or CD40 ligand in conjunction with IL-4. 788 6

We have studied the TCR mediated signal transduction pathways involved in transcriptional regulation of the mouse IL-4 gene. The sequences extending from base pair -766 to +63 of the IL-4 gene were inserted upstream of a luciferase indicator gene. Transcriptional activity was observed when the construct, [pIL-4(-766)], was transfected into either the IL-4 producing cell line, EL-4, or the IL-4 non-producing T cell hybridoma, 68-41, but not in the L929 fibroblast cell line. By analysis of deletion mutants of pIL-4(-766), we identified a transcriptional regulatory element that is tightly associated with a signal coming from the TCR and which controls inducible activation of the IL-4 promoter. By analysis of deletion mutants of pIL-4(-766), this latter element was found between base pairs -147 to -17. Electrophoretic mobility shift assays indicated that expression of a nuclear binding protein with binding sites between base pairs -84 and -55 could be induced. By competition and mutation analysis, the binding motif of this protein was determined to be AAAATTTTCC. Stimulation with ionomycin alone was sufficient to induce activity in pIL-4(-766). Cyclosporin A inhibited both the IL-4 promoter activity and activation of the inducible nuclear protein. Transient over-expression of a constitutively active form of the Ca2+/calmodulin-regulated protein phosphatase, calcineurin was sufficient to cause activation of pIL-4(-766) without any additional stimulus. These results indicate that the signaling requirements for activation of upstream positive regulatory elements of the IL-4 gene are distinct from those of the IL-2 gene. Ca2+ mobilization is sufficient to activate the IL-4 promoter, whereas IL-2 gene transcription requires both Ca2+ mobilization and protein kinase C activation.
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PMID:The Ca2+/calmodulin-activated, phosphoprotein phosphatase calcineurin is sufficient for positive transcriptional regulation of the mouse IL-4 gene. 815 95

During screening for inhibitors of T cell activation, we have found that trichostatin A (TSA), known as a potent inhibitor of histone deacetylase, showed selective inhibitory activity against IL-2 gene expression. From luciferase reporter experiments on human leukemic Jurkat T cells, TSA was found to inhibit the expression of the luciferase reporter gene directed by the IL-2 enhancer and promoter with a 50% inhibitory concentration value of 0.073 microM. On the other hand, TSA, at the same concentration, enhanced the expression of the luciferase reporter gene directed by the c-fos enhancer and promoter. The result of RT-PCR experiments also indicates that TSA has selective inhibitory activity against IL-2 gene expression in Jurkat cells. These results suggest that the change in chromatin structure caused by the hyperacetylation of histone might affect the regulation of IL-2 and c-fos gene expression.
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PMID:Selective inhibition of IL-2 gene expression by trichostatin A, a potent inhibitor of mammalian histone deacetylase. 868 22

Ligand binding to cytokine receptors rapidly triggers tyrosine phosphorylation of Janus family tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Jak2 activation is mediated by PRL receptor homodimers as well as by receptors for the interleukin (IL)-3, IL-5, and granulocyte macrophage-colony stimulating factor, which share the common beta c-subunit. Otherwise, Jak1 and Jak3 are involved in IL-2 signaling through heterodimerization of the IL-2 receptor-beta (IL-2R beta) and gamma c-chains. Stat5, a member of the Stat family, confers the PRL response on milk protein genes. Here we show that chimeric PRL receptors that contain the transmembrane and cytoplasmic domains of the IL-2R beta or beta c-chains transduce in response to PRL tyrosine phosphorylation and activation of Jak1 and Jak2, respectively. Tyrosine phosphorylation of Stat5, activation of its DNA-binding activity assessed in bandshift experiments using a lactogenic hormone responsive region (LHRR) probe, and transcriptional induction of a beta-casein promoter luciferase construct in stably transfected CHO cells are observed with both chimeras upon PRL stimulation. Our results demonstrate that distinct cytoplasmic domains of these cytokine receptors elicit convergent signaling pathways and provide evidence that beta c and IL-2R beta function as a complete signal transducer. Our data strengthen previous observations that Stat5 activation is not dependent on the activation of a specific Jak kinase and also suggest that neither Jak3 nor gamma c have a specific role in this process.
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PMID:Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription. 872 89

IL-15 is a newly identified cytokine that has T cell and B cell growth factor activity similar to that of IL-2. In this study, a novel biologic function of IL-15 to promote cytokine production by human Th cells has been elucidated. Dermatophagoides farinae 11 (a major allergen of house dust mite)-specific human T cell clones produced IL-5 in response to recombinant human IL-15 as well as to either anti-CD3 or IL-2 stimulation. IL-5 mRNA became detectable 3 h after IL-15 stimulation and reached a maximum at 9 h. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was clearly transcribed in response to IL-15, indicating that the approximately 500-bp human IL-5 promoter/enhancer segment 5' upstream of the coding region sufficiently responded to IL-15. IL-15-induced IL-5 synthesis was completely inhibited by the tyrosine kinase inhibitor, herbimycin A, suggesting the involvement of tyrosine kinases in the signal transduction leading to IL-5 synthesis as well as to proliferation of T cells induced by IL-15. Whereas IL-5 production by human peripheral T cells was abolished by the addition of anti-IL-2-neutralizing Abs into the culture, IL-15 restored the IL-5 synthesis despite effective IL-2 neutralization. IL-15 produced at the site of allergic inflammation may play a role in the recruitment and activation of eosinophils by inducing IL-5 (a Th2 cytokine) production by T cells.
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PMID:IL-15 promotes cytokine production of human T helper cells. 878 97

The role of IL-2 in IL-5 synthesis of human helper T cells was investigated. All of the Der f II (a major allergen of house dust mite)-specific T cell clones established from atopic asthmatic patients produced both IL-2 and IL-4 upon activation (Th0 phenotypes). Recombinant IL-2 induced gene expression and protein synthesis of IL-5 in T cell clones that produced IL-5 upon antigenic stimulation. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was clearly transcribed in response to IL-2, indicating that the approximately 500 bp gene segment 5' upstream of the coding region was functionally sufficient for the gene transcription induced by IL-2. IL-2-induced IL-5 synthesis as well as proliferation was dependent on tyrosine kinases. Moreover, IL-5 production by T cell clones stimulated with immobilized anti-CD3 antibody was completely abrogated by anti-IL-2 neutralizing antibody, suggesting that IL-5 (a Th2 cytokine) synthesis of human helper T cells is dependent on IL-2 (a Th1 cytokine). Our present findings clearly demonstrated that IL-2, known as a T cell growth factor, exerts a cytokine promoting activity on T cells. IL-2 produced at the site of allergic inflammation might facilitate eosinophilic inflammation by inducing IL-5 production in T cells.
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PMID:A critical role of IL-2 for the production and gene transcription of IL-5 in allergen-specific human T cell clones. 898 73

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) for the initiation of antigen-specific T-cell activation. DCs may be highly enriched from peripheral blood-adherent leukocytes by short-term (7-day) culture in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. Various methods of gene transfer were studied, including DNA/liposome complexes, electroporation, CaPO4 precipitation, and recombinant adenovirus (AdV) vectors. Low levels of expression were obtained with the physical methods tested. In contrast, AdV vectors expressing luciferase, beta-galactosidase, IL-2, and IL-7 all readily transduced human DCs. Increasing levels of gene expression were observed over a range of multiplicity of infection (MOI) of 10:1 to 10,000:1, with transduction efficiencies exceeding 95% at higher MOI. Although levels of maximal gene expression in DCs were significantly lower than those obtained using human tumor cell lines, IL-2 and IL-7 production of up to 5 x 10(2) ng/10(6) DC were achieved. These results suggest that AdV vectors are a promising vehicle for genetically engineering human DCs.
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PMID:A comparison of gene transfer methods in human dendritic cells. 901 47


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