Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cloned murine interleukin 3 (IL 3)-dependent cell lines FD.C/1, 32Dc1-23, and KP3 can each be switched to interleukin 2 (IL 2)-dependent growth states. Replication-defective retroviral vectors have been used to introduce the v-src oncogene into each of these cell lines maintained in either an IL 3- or an IL 2-dependent growth state. These cell lines maintained in an IL 3-dependent growth state were converted to lymphokine-independent growth after infection with v-src. These same cells maintained in an IL 2-dependent growth state and infected with v-src maintained strict lymphokine dependence for growth. Another cloned murine IL 3-dependent cell line, GM, can be switched to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent growth state. GM cells maintained as IL 3- or GM-CSF-dependent cells readily converted to a lymphokine-independent growth state when infected with v-src. These experiments indicate that either there exist differences in the biochemical mechanisms of signal transduction through the IL 3- and IL 2-specific receptors, or developmental processes associated with the switching of cells to an IL 2-dependent growth state influence expression of the v-src gene product. These cell lines offer new ways not only for analyzing biochemical pathways that regulate cell growth, but also for analyzing the control of oncogene expression.
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PMID:Effect of infection with murine recombinant retroviruses containing the v-src oncogene on interleukin 2- and interleukin 3-dependent growth states. 349 96

Two growth factors, interleukin 2 (T cell growth factor) and colony-stimulating factor, are produced concomitantly by a murine EL-4 thymoma cell line after stimulation by phorbol myristate acetate. As shown elsewhere, these thymoma-derived factors appear to be biochemically and functionally indistinguishable from the interleukin 2 and colony-stimulating factor produced by mitogen-stimulated mouse spleen cells. Both factors co-elute during gel filtration with apparent m.w. in the range of 30,000, and both exhibit overlapping isoelectric point profiles between pH 4 and pH 5. Because we were unable to separate these 2 factors by methods based on either m.w. or charge, we have used phenyl-Sepharose chromatography, a method based on hydrophobic interactions, to completely separate murine interleukin 2 and colony-stimulating factor. In contrast with published reports, each of the separated factors exhibits unique biologic activities on lymphocytes and macrophages. Interleukin 2 provides help for antibody synthesis in the nude mouse, but neither enhances interferon production by macrophages nor stimulates macrophage growth. Colony-stimulating factor does not enhance antibody synthesis in the nude mouse but does enhance interferon production by macrophages and stimulate macrophage growth.
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PMID:Biologic properties of chromatographically separated murine thymoma-derived Interleukin 2 and colony-stimulating factor. 617 Jun 82

A helper factor (CHF) necessary for the generation of primary allospecific CTL using BALB/c (H-2d) responder spleen cell and x-irradiated RDM4 (H-2k) stimulator tumor cells was obtained from cultures of mouse spleen cells stimulated for the production of secondary anti-Sendai virus CTL and fractionated by gel filtration chromatography to obtain a 30,000 m.w. species (CHF30). DEAE-cellulose chromatography separated CHF activity from the majority of interleukin 1 (IL 1), interleukin 2 (IL 2), granulocyte-macrophage colony-stimulating factor (CSF), and interferon (IFN). Interleukin 3 (IL 3) and CHF co-eluted when this procedure was used. Reverse-phase high performance liquid chromatography (HPLC) of CHF30 with a variety of elution conditions allowed the separation of CHF activity from IL 1, IL 2, IL 3, CSF, and IFN. IL 3 and CSF in the CHF30 preparation were stable at 80 degrees C for more than an hour, whereas CHF activity decreased rapidly during the first 10 min of incubation. Trypsin treatment of the same material showed that CHF activity was resistant to digestion for 40 min, whereas IL 3 and CSF lost most of their activities during the first 5 min of incubation. These results indicate that CHF activity is mediated by molecules biologically and biochemically distinct from the well characterized cytokines.
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PMID:Chromatographic separation from known cytokines of a helper factor necessary for the generation of murine cytolytic T lymphocytes. 619 15

The effects of pure and crude human urinary erythropoietin, crude sheep plasma erythropoietin and other growth factors on the incorporation of labeled thymidine were studied using spleen cells from mice previously treated with phenylhydrazine hydrochloride. Erythropoietin at 400 mU/ml caused a 40-80 fold increase in the incorporation of the labeled nucleoside. The slope of the dose-response curve found for pure erythropoietin was not significantly different from that found for a crude urinary erythropoietin preparation or for crude sheep plasma erythropoietin. Colony-stimulating factor, interleukin 2, interleukin 3 and the lectin, concanavalin A were also stimulatory but at concentrations from one hundred to one million times higher than that found for erythropoietin.
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PMID:The effect of erythropoietin and other factors on DNA synthesis by mouse spleen cells. 660 86

The frequencies of precursors of C57BL/6 T lymphocytes that respond to DBA/2 alloantigens by secreting the lymphokines interleukin 2 (IL-2), macrophage-activating factor (MAF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been directly compared with cytolytic T lymphocyte precursor (CTL-P) frequencies in limiting dilution microcultures established from spleen cells positively or negatively selected on the basis of Lyt-2 phenotype. A clear dichotomy was observed between CTL-P, which were contained in the Lyt-2+ fraction, and precursors of IL-2-secreting cells, which were detected almost exclusively in the Lyt-2- population. In contrast, precursors of cells secreting MAF and GM-CSF were found in both populations: almost all responding cells from the Lyt-2- fraction produced both these factors, whereas the precursor frequency of MAF-secreting and GM-CSF-secreting cells was three- to fourfold lower in the Lyt-2+ population. These frequency data were consistent with quantitative differences observed in the average production of these lymphokines by Lyt-2+ and Lyt-2- populations.
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PMID:Precursor frequency analysis of lymphokine-secreting alloreactive T lymphocytes. Dissociation of subsets producing interleukin 2, macrophage-activating factor, and granulocyte-macrophage colony-stimulating factor on the basis of Lyt-2 phenotype. 675 27

T-lymphocyte proliferation is suppressed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, and is associated with a decrease in interleukin 2 (IL-2), gamma interferon, and granulocyte-macrophage colony-stimulating factor mRNA levels. We report here that 1,25(OH)2D3-mediated repression in Jurkat cells is cycloheximide resistant, suggesting that it is a direct transcriptional repressive effect on IL-2 expression by the vitamin D3 receptor (VDR). We therefore examined vitamin D3-mediated repression of activated IL-2 expression by cotransfecting Jurkat cells with IL-2 promoter/reporter constructs and a VDR overexpression vector and by DNA binding. We delineated an element conferring both DNA binding by the receptor in vitro and 1,25(OH)2D3-mediated repression in vivo to a short 40-bp region encompassing an important positive regulatory element, NF-AT-1, which is bound by a T-cell-specific transcription factor, NFATp, as well as by AP-1. VDR DNA-binding mutants were unable to either bind to this element in vitro or repress in vivo; the VDR DNA-binding domain alone, however, bound the element but also could not repress IL-2 expression. These results indicate that DNA binding by VDR is necessary but not sufficient to mediate IL-2 repression. By combining partially purified proteins in vitro, we observed the loss of the bound NFATp/AP-1-DNA complex upon inclusion of VDR or VDR-retinoid X receptor. Order of addition and off-rate experiments indicate that the VDR-retinoid X receptor heterodimer blocks NFATp/AP-1 complex formation and then stably associates with the NF-AT-1 element. This direct inhibition by a nuclear hormone receptor of transcriptional activators of the IL-2 gene may provide a mechanistic explanation of how vitamin derivatives can act as potent immunosuppressive agents.
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PMID:Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. 756 32

It has been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce specific and non-specific anti-tumour cytotoxicity and also stimulates the proliferation and function of peripheral lymphocytes and thymocytes. GM-CSF and interleukin 2 (IL-2) act synergistically on peripheral lymphocytes for the induction of a highly effective cytotoxic cell population. Thus, the goal of our investigation was to study the effects of GM-CSF upon expansion, proliferation and in vitro killing activity of tumour-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC). TILs from seven consecutive tumours were cultured with GM-CSF (500 or 1000 nmol ml-1) without IL-2 supplementation, with suboptimal doses of IL-2 (8 and 40 U ml-1) plus GM-CSF (1000 nmol ml-1), and with a dose of IL-2 (400 U ml-1) which sufficed alone to induce TIL development plus GM-CSF (500 or 1000 nmol ml-1). GM-CSF alone or together with suboptimal doses of IL-2 was not able to induce or facilitate TIL development in these cultures. When GM-CSF at both concentrations studied was added to optimal doses of IL-2 the resulting TIL populations proliferated significantly better and faster (+66%), resulting in a higher cell yield (+24%) at the time of maximal expansion of the TIL cultures. The length of the culture periods of TILs was not affected by GM-CSF when compared with the control cultures supplemented with IL-2 alone. In vitro killing activity of TIL populations stimulated with IL-2 and GM-CSF remained unspecific, but lysis of the autologous tumour targets as well as the allogeneic renal tumour targets was significantly enhanced (+138%) as compared with the corresponding control TILs stimulated with IL-2 alone. Lysis of the natural killer (NK)-sensitive control cell line K562 and the NK-resistant Daudi cell line remained unchanged even though FACS analysis of TILs cultured with IL-2 and 1000 nmol of GM-CSF demonstrated a significantly higher proportion of cells expressing the CD56 molecule (+50%). Specific receptors for GM-CSF could not be demonstrated on TILs from RCC. Our data demonstrate that GM-CSF alters the biological behaviour of IL-2-activated TILs from renal cell carcinoma in terms of proliferation, in vitro killing activity and cell-surface molecule expression.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effects of granulocyte-macrophage colony-stimulating factor on tumour-infiltrating lymphocytes from renal cell carcinoma. 759 37

Knowing how mycobacteria exploit host cytokines to survive and which cytokines have important roles in host defense against mycobacteria should allow the use of these molecules in the treatment of mycobacterial infections. Both interleukin 2 and interferon gamma have been used to treat patients with leprosy, and granulocyte-macrophage colony-stimulating factor is presently being administered to AIDS patients infected with Mycobacterium avium.
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PMID:Recombinant cytokines for controlling mycobacterial infections. 771 35

Cancer vaccines genetically engineered to produce interleukin 2 have been investigated intensively in a series of animal models and are at the point of entering into clinical trials. In this study we demonstrate a strong correlation between the rate of interleukin 2 production and the protection efficiency of murine S91 melanoma cell (clone M-3) vaccines. Best immunization is achieved with vaccines producing medium interleukin 2 levels of 1000-3000 units per 10(5) cells per day. Reduced interleukin 2 production evokes a corresponding decline in the number of successfully treated animals. Unexpectedly, when interleukin 2 expression is raised to high levels of 5000-7500 units per 10(5) cells per day, protection is completely absent because of impaired generation of tumor-specific cytotoxic T lymphocytes. In comparison, granulocyte-macrophage colony-stimulating factor as immunomodulator induces substantial immunization even at a moderate level of secretion and protects all animals at the maximal obtainable level of secretion. Our findings demonstrate the importance of the interleukin 2 level produced by genetically modified tumor cells and may have substantial impact for the clinical application of cancer vaccines.
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PMID:Cancer vaccines: the interleukin 2 dosage effect. 775 70

Cytokines manifest their function through alteration of gene expression. However, target genes for signals from cytokine receptors are largely unknown. We therefore searched for immediate-early cytokine-responsive genes and isolated a novel gene, CIS (cytokine inducible SH2-containing protein) which is induced in hematopoietic cells by a subset of cytokines including interleukin 2 (IL2), IL3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO), but not by stem cell factor, granulocyte colony-stimulating factor and IL6. The CIS message encodes a polypeptide of 257 amino acids that contains an SH2 domain of 96 amino acids in the middle. To clarify the function of CIS in cytokine signal transduction, we expressed CIS in IL3-dependent hematopoietic cell lines under the control of a steroid-inducible promoter. The CIS product stably associated with the tyrosine-phosphorylated beta chain of the IL3 receptor as well as the tyrosine-phosphorylated EPO receptor. Forced expression of CIS by steroid reduced the growth rate of these transformants, suggesting a negative role of CIS in signal transduction. CIS induction requires the membrane-proximal region of the cytoplasmic domain of the EPO receptor as well as that of the common beta chain of the IL3, IL5 and GM-CSF receptor, whereas CIS binds to the receptor that is tyrosine phosphorylated by cytokine stimulation. Thus CIS appears to be a unique regulatory molecule for cytokine signal transduction.
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PMID:A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. 779 8


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