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 K562 cell line provides a unique population of primitive human myeloid leukaemia cells which can be induced to differentiate along the erythroid, granulocytic, macrophage and megakaryocytic lineages in response to several agents. Cytarabine is not only the most widely used drug in the treatment of myeloid leukaemia but also the most effective agent in K562 cells. The effects of five recombinant human cytokines - interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-alpha, interferon-beta and interferon-gamma on cytarabine-induced growth inhibition and differentiation of K562 cells was studied in liquid suspension cultures. GM-CSF and to a lesser extent IL-3 enhanced the antiproliferative effect of cytarabine in K562 cells, whereas the three interferons reduced it. The efficacy of cytarabine in inhibiting the growth of K562 cells was doubled by its combination with GM-CSF or IL-3 but was halved by its combination with interferons. The five cytokines did not significantly affect cytarabine-induced erythroid differentiation of K562 cells. The present results appear to favour the use of GM-CSF and IL-3 but not of interferons in future treatment strategies based on a combined cytokine and chemotherapy approach for myeloid leukaemia.
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PMID:Effects of recombinant human cytokines on cytarabine activity in K562 human myeloid leukaemia cells. 176 Sep 44

The effects of interferon-gamma (IFN-gamma) on a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) were assessed. When added with myeloid growth factors (interleukin-3 [IL-3], granulocyte-macrophage colony-stimulating factor [GM-CSF], or macrophage-CSF [M-CSF]), IFN-gamma inhibited the formation of colonies in soft agar assays. Furthermore IFN-gamma stimulated an increase in the number of macrophages present in colonies formed in the presence of IL-3. IFN-gamma also inhibited M-CSF-, GM-CSF-, or IL-3-stimulated [3H]-thymidine incorporation in highly enriched GM-CFC. However, when added in the absence of hematopoietic growth factors, IFN-gamma promoted the survival of GM-CFC and had a modest stimulatory effect on DNA synthesis. The direct interaction of the IFN with GM-CFC was confirmed by showing its ability to rapidly activate the sodium/hydrogen antiport in GM-CFC, as do the mitogens GM-CSF, M-CSF, and IL-3. However, the effect of IFN-gamma on intracellular pH and DNA synthesis was transient and pretreatment with IFN markedly inhibited the ability of GM-CSF, M-CSF, and IL-3 to activate the sodium/hydrogen antiport. IFN-gamma has a dual effect on GM-CFC, decreasing the rate of cell death but also limiting the proliferative response to CSFs.
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PMID:Interferon-gamma stimulates the survival and influences the development of bipotential granulocyte-macrophage colony-forming cells. 182 54

Antileishmanial defense has been ascribed to the antimicrobial effects induced by soluble macrophage-activating lymphokines (MAFs), such as interferon-gamma and granulocyte-macrophage colony-stimulating factor. Recently, we identified an additional mechanism of T cell-mediated macrophage activation of defense against Leishmania that is apparently lymphokine independent, requires cell-cell contact, and is not cytotoxic to host cells. By employing antigen-specific murine T cell hybridoma lines, we observed that this property was associated with CD4+ subpopulations possessing the characteristics of the Th1 subset. In the present study, we address the question of whether contact-mediated macrophage activation can also be induced by Th2 lymphocytes. We employed as T effector cells in antileishmanial defense assays the Th2 cell line D10.G1.4 (D10) which is specific for conalbumin. We observed that D10 cells were able to induce activation of Leishmania-infected macrophages only when the macrophages were also primed with conalbumin, and that this activation apparently occurred by a mechanism without the secretion of MAF. Moreover, when mice infected with L. major were injected into footpad lesions with conalbumin and D10 cells, in situ parasite replication was partially inhibited. The expression of this antimicrobial mechanism by Th1 as well as Th2 clones suggests that the property of contact-mediated (lymphokine-independent) activation may be shared by certain lymphocytes in both Th1 and Th2 subpopulations. We hypothesize that this activation mechanism may involve the interaction of a lymphocyte membrane-associated MAF (such as tumor necrosis factor) and its receptor on the infected macrophage, resulting in the induction of antimicrobial effects but not cytotoxicity to the host cell.
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PMID:Th2 lymphocyte clone can activate macrophage antileishmanial defense by a lymphokine-independent mechanism in vitro and can augment parasite attrition in vivo. 182 32

Granulocyte-macrophage colony-stimulating factor (GM-CSF) raised the plasminogen activator (PA) activity of cultured human monocytes. This activity was characterized to be urokinase-PA (u-PA) by incubation with specific IgG and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. Increased u-PA activity reflected GM-CSF-induction of u-PA mRNA levels. The stimulatory properties of GM-CSF for monocyte PA activity differed from those of interleukin-4, which induced monocyte tissue-type PA (t-PA) activity, and of interferon-gamma (IFN-gamma), which alone was not stimulatory but augmented lipopolysaccharide-induced t-PA activity. GM-CSF alone did not stimulate detectable monocyte t-PA activity but combined with IFN-gamma to promote this activity. Plasmin formation arising from GM-CSF-induced u-PA in monocytes may contribute to the matrix turnover involved in, eg, cell migration and inflammation, and may explain some of the pathology seen in GM-CSF transgenic mice.
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PMID:Activation of human monocytes by granulocyte-macrophage colony-stimulating factor: increased urokinase-type plasminogen activator activity. 189 23

The aim of the present study was to compare the response of bone marrow (BM) lymphocytes from patients with aplastic anemia (AA) or normal controls to increasing doses of antilymphocyte globulin (ALG) or phytohemagglutinin (PHA). For this purpose BM T-enriched cells from 11 AA patients and 9 normal individuals were incubated with ALG (0-1000 micrograms/ml) or PHA (0%-10%) for 1 day, and the supernatants were tested for suppression/enhancement of granulocyte-macrophage colony-forming unit (CFU-GM) growth and for release of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) assayed with the enzyme-amplified sensitivity immunoassay (EASI). The production of colony-stimulating activity (CSA) by T cells primed with ALG and tested in the absence of exogenous GM-CSF correlated with the dose of ALG in priming cultures up to 14% EG (100% EG = CFU-GM growth with 30 ng/ml of GM-CSF). The amount of GM-CSF in the supernatants paralleled their capacity to sustain CFU-GM growth (up to 3.5 ng/ml of GM-CSF). Production of CSA or GM-CSF from T cells primed with PHA was significantly lower. Supernatants of PHA-primed T cells, when added to normal BM cells in the presence of exogenous GM-CSF, produced a dose-dependent inhibition of CFU-GM growth (down to 13% +/- 10% EG). The same supernatants contained detectable amounts of IFN-gamma and TNF-alpha (21 +/- 6.7 IU/ml and 4.6 +/- 2.9 ng/ml, respectively). IFN-gamma production from severe AA (SAA) T cells in response to PHA was significantly superior to the IFN-gamma production from normal T cells (21 +/- 6.7 IU/ml vs 9.5 +/- 7.1 IU/ml, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro response of T cells from aplastic anemia patients to antilymphocyte globulin and phytohemagglutinin: colony-stimulating activity and lymphokine production. 190 92

We have previously reported that cultured human monocytes are lysed by autologous lymphokine-activated killer (LAK) cells in vitro and that treatment of monocytes with interferon-gamma (IFN-gamma) decreased their sensitivity to lysis. Conversely, incubation of monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhanced their susceptibility to LAK-mediated cytotoxicity. To determine if certain antigens were differentially modulated on macrophages by IFN-gamma and GM-CSF, cytokine-treated and untreated monocytes were analyzed for the expression of a variety of cell surface markers by flow cytometry. Cytotoxicity assays were performed to assess the ability of antibodies to each of these markers to block LAK lysis of macrophage target cells. While several of the surface structures were differentially modulated by cytokine treatment, it was found that only monoclonal antibodies to the adhesion proteins CD11a and CD18 were capable of blocking lysis of either cytokine-treated or untreated target macrophages.
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PMID:Differential modulation of surface antigens on human macrophages by IFN-gamma and GM-CSF: effect on susceptibility to LAK lysis. 190 35

We investigated the effects of several cytokines on HLA-DR expression in cultured fibroblasts derived from retroocular connective tissue and pretibial and abdominal skin of patients with Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD), as well as from normal individuals. We hypothesized that differences in response to cytokines between fibroblasts from various anatomical areas might play a role in the site-selective involvement of the extrathyroidal manifestations of Graves' disease. HLA-DR expression in fibroblasts was quantitated by scanning densitometry of whole cell lysates subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Direct immunofluorescence of cell monolayers was also performed. We hypothesize that unique characteristics of these fibroblasts may play a role in GO and PTD. Cultured retroocular, pretibial, and abdominal fibroblasts from patients with Graves' disease as well as from normal individuals did not express HLA-DR spontaneously. Treatment in vitro with interferon-gamma (IFN gamma; 100 U/mL) for 5 days induced HLA-DR by 50- to 80-fold (P less than 0.0001) in fibroblasts from all sites and subjects studied. However, IFN gamma-induced HLA-DR expression was significantly greater in retroocular (P less than 0.005) and pretibial (P less than 0.0005) fibroblasts from patients with GO and PTD than in fibroblasts obtained from the same anatomical sites of normal individuals. Further, retroocular and pretibial fibroblasts from patients with GO and PTD responded to IFN gamma more vigorously than did abdominal fibroblasts from these same patients (P less than 0.0001). IFN gamma-induced HLA-DR expression was enhanced by concomitant treatment with tumor necrosis factor-alpha (100 U/mL). In contrast, treatment of retroocular fibroblasts with transforming growth factor-beta (10 ng/mL), epidermal growth factor (1 ng/mL), or interleukin-6 (IL-6; 100 U/mL) significantly attenuated IFN gamma-induced HLA-DR reactivity by 40-59% (P less than 0.05). Incubation of retroocular fibroblasts with tumor necrosis factor-alpha, IL-1 alpha (10 U/mL), IL-2 (10 U/mL), IL-6, granulocyte-macrophage colony-stimulating factor (100 U/mL), epidermal growth factor, and transforming growth factor-beta alone did not affect HLA-DR expression. These results indicate that several cytokines can influence HLA-DR expression in cultured fibroblasts. The enhanced induction of HLA-DR by IFN gamma in retroocular and pretibial fibroblasts compared with that in abdominal fibroblasts may partially explain the selective involvement of the retroocular connective tissue and pretibial skin in fully expressed Graves disease.
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PMID:Increased induction of HLA-DR by interferon-gamma in cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial dermopathy. 190 94

Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a growth factor for granulocytes and macrophages, is an activator of cells of the monocyte/macrophage lineage and induces HLA class II expression and cytokine synthesis in these target cells. Macrophage activation and class II expression are prominent features in rheumatoid arthritis (RA) joints, but the mechanism of their stimulation is not understood, since interferon-gamma, the major stimulus of class II expression, is not usually detectable at the protein level in synovial cell culture supernatants. We have, therefore, studied GM-CSF expression in cultures of cells derived from joints affected by RA and osteoarthritis (OA), and show that GM-CSF is produced spontaneously both by RA synovial cells and to a lesser extent by OA synovial cells in the absence of extrinsic stimuli. GM-CSF production continues for the 5-day duration of the culture period. Using neutralizing antibodies to tumor necrosis factor (TNF)-alpha we demonstrated that GM-CSF production in RA synovial cell cultures is dependent on the continued presence of active TNF-alpha. This result supports our concept that continued activation of the cytokine network is a marked feature of RA, and that TNF-alpha plays a pivotal role in this network, by regulating the production of other pro-inflammatory cytokines, such as interleukin 1, as demonstrated previously, and GM-CSF.
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PMID:Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. 191 59

A macrophage migration inhibitory factor (MIF) was purified to homogeneity from the serum-free culture supernatant of a human T cell hybridoma clone called F5. This clone was established by means of somatic fusion, using the emetine-actinomycin D selection method, and produced a large amount of MIF. The MIF activity in the culture supernatant of F5 cells was not due to contaminating interferon-gamma (IFN-gamma), which is known to possess MIF activity. Furthermore, other known cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF), were also revealed to have MIF activity, but our MIF was different from these known factors. F5 cells produced two species of MIF that could be separated on a phenyl-Sepharose column. MIF-1 (the more hydrophilic species of the two) was purified to homogeneity by sequential hydrophobic chromatography, ion-exchange chromatography, dye ligand affinity chromatography, and high-performance liquid chromatography (HPLC) on ion-exchange and reverse-phase columns. Finally, 4600-fold enrichment, as to specific activity, of MIF-1 was achieved. The purified MIF-1 was digested with endoproteinase Lys-C into some peptide fragments and the amino acid sequences of the peptides obtained were determined. No sequence identity between our MIF-1 and other proteins was observed. Then, antibodies were raised against a peptide synthesized according to the determined amino acid sequence. They specifically reacted with MIF-1 and reduced its migration inhibitory activity. Based on these results, we conclude that the determined amino acid sequence was certainly that of MIF-1.
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PMID:Macrophage migration inhibitory factor (MIF) produced by a human T cell hybridoma clone. 193 71

Selective mRNA degradation is an important control point in the transient expression of a variety of mRNAs coding for growth regulators. A variety of labile mRNAs coding for lymphokines, cytokines, and oncogenes contain within their 3'-untranslated region an AU-rich region shown to destabilize these messages. We recently identified a cytosolic protein, adenosine-uridine binding factor (AUBF), which complexes with four tandem AUUUA reiterations of a synthetic RNA transcript. We now show that AUBF forms RNase T1-resistant band-shifted complexes with a variety of in vitro transcribed mRNAs including granulocyte-macrophage colony-stimulating factor, interferon-gamma, interleukin-3, c-fos, and v-myc. Formation of complexes was specifically inhibited by AUUUA containing RNA, but not by irrelevant RNA. After brief ultraviolet light-induced cross-linking, AUBF.RNA complexes with the exception of c-fos comigrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Mutations within the AUUUA motifs demonstrate that both nucleotide sequence and secondary structure are important in AUBF.AUUUA RNA complex formation. Based upon these data, we suggest AUBF may interact with a variety of labile mRNAs with multiple AUUUA reiterations or single reiterations within an AU-rich 3'-untranslated region.
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PMID:The adenosine-uridine binding factor recognizes the AU-rich elements of cytokine, lymphokine, and oncogene mRNAs. 199 89


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