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 effects of hematopoietic growth factors on in vitro human megakaryocytopoiesis were studied using a serum-depleted culture system. Both recombinant interleukin-3 (r-IL-3) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) increased megakaryocyte (MK) colony formation (P less than .01) above that observed in baseline cultures. Recombinant interleukin-4 (rIL-4) and interleukin 1 alpha (rIL-1 alpha) failed either to promote MK colony formation alone or to increase rIL-3 or rGM-CSF promoted colony formation. Recombinant erythropoietin (rEpo) and purified thrombocytopoiesis-stimulating factor (TSF) did not increase (P greater than .05) MK colony formation when added alone but synergized with rIL-1 alpha, leading to a twofold increase in MK colony formation. Such a synergistic relationship was not observed between rIL-4 and rEpo. In addition, TSF enhanced the ability of rIL-3 but not rGM-CSF to promote MK colony formation. Addition of rEpo to optimal or suboptimal concentrations of rGM-CSF or suboptimal concentrations of rIL-3 resulted in a significant increase (P less than .05) in the total number of MK-containing colonies, due to the appearance of multilineage colonies containing MKs. The addition of rEpo to optimal concentrations of rIL-3 resulted in increased numbers of multilineage colonies containing MKs; however, the number of total MK-containing colonies was not significantly increased when compared to assays containing rIL-3 alone. By contrast, transforming growth factor-beta (TGF-beta) inhibited both rIL-3, and rGM-CSF promoted MK colony formation, with optimal inhibition resulting in a 35%-45% reduction of MK colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interacting cytokines regulate in vitro human megakaryocytopoiesis. 264 84

We have studied the possible role of various cytokines and growth factors on the in vitro interleukin-2 (IL-2)-dependent development of natural killer (NK) cells from bone marrow precursors. Our results indicate that tumor necrosis factor alpha and lymphotoxin augment the generation of NK cells. In contrast, interleukin-4, transforming growth factor beta and granulocyte-macrophage colony-stimulating factor significantly inhibit this phenomenon. Other factors tested, such as epidermal growth factor and fibroblast growth factor, did not detectably influence the IL-2-dependent development of NK cells.
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PMID:Effect of various cytokines and growth factors on the interleukin-2-dependent in vitro differentiation of natural killer cells from bone marrow. 265 22

By immunoblotting with antibodies for phosphotyrosine, we have demonstrated that the hematopoietic growth factors interleukin-2, interleukin-3, interleukin-4, and granulocyte-macrophage colony-stimulating factor stimulate the tyrosine phosphorylation of specific sets of proteins in murine hematopoietic progenitor cell lines. The stimulation of tyrosine phosphorylation is a receptor-dependent transient event. The effect of these hematopoietic growth factors on protein tyrosine phosphorylation was not mediated through protein kinase C.
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PMID:Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3-dependent murine cell lines. 326 Mar 30

Interleukin-4 induced the formation of foreign body-type giant multinucleated cells from human monocyte-derived macrophages, an effect that was optimized with either granulocyte-macrophage colony-stimulating factor or interleukin-3, dependent on the concentration of interleukin-4, and specifically prevented by anti-interleukin-4. Very large foreign body giant cells and, predominantly, giant cell syncytia with randomly arranged nuclei and extensive cytoplasmic spreading (285 +/- 121 nuclei and 1.151 +/- 0.303 mm2 per syncytium) were consistently obtained. Under otherwise identical culture conditions, relatively much smaller Langhans-type giant cells with circularly arranged nuclei were induced with a previously described combination of interferon-gamma plus granulocyte-macrophage colony-stimulating factor or interleukin-3 (16 +/- 6 nuclei and 0.033 +/- 0.013 mm2 per giant cell); their formation was prevented by anti-interferon-gamma but not by anti-interleukin-4. Similar rates of macrophage fusion were obtained in both culture systems (72 +/- 5% and 74 +/- 6%, respectively), but these two morphological variants did not occur simultaneously or form from one another within the 10-day culture period. These findings demonstrate that interleukin-4 is a potent human macrophage fusion factor and that differential regulation of macrophage fusion by interleukin-4 and interferon-gamma may lead to morphological variants of multinucleated giant cells.
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PMID:Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells. 748 11

T-helper cells can differentiate into at least two subtypes secreting distinct profiles of cytokines, Th1 and Th2, regulating immunoprotection and different immunopathologies. Interleukin-4 (IL-4) is both the product and the inducer of Th2 cells, raising the question whether IL-4 can be produced in response to antigen-independent stimuli. Here we show that human basophils produce IL-4 on stimulation with IL-3 and C5a or C5adesarg in similar amounts as induced by IgE-receptor-cross-linking. C5a-induced IL-4 production requires the presence of IL-3, with little effect of the sequence of stimuli addition. No "Th1-cytokines" (interferon-gamma and IL-2) and even no "Th2-cytokines" (IL-3, IL-5, IL-10, and granulocyte-macrophage colony-stimulating factor) are produced by basophils in response to either IgE-dependent or IgE-independent activation. The generation of leukotriene C4 (LTC4) is regulated in a similar manner. However, C5a induces a rapid, transient burst of leukotriene formation only if added after IL-3. Interestingly, upon prolonged culture, a late phase of continuous LTC4 production is observed, which also requires two signals (IL-3 and C5a), but rather depends on their continuous presence than on their sequence of action. These data describe an antigen-independent pathway of very restricted IL-4 expression. Thus, basophils must be considered as central immunoregulatory cells of the innate immune system. Furthermore, the results show that LTC4 can also be generated more continuously for many hours, a phenomenon that may be of particular importance in chornic allergic inflammation, such as asthma.
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PMID:IgE-independent interleukin-4 expression and induction of a late phase of leukotriene C4 formation in human blood basophils. 749 59

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on cytokine profile was evaluated in a case of severe congenital neutropenia. The plasma levels of cytokines were measured before and during rhG-CSF therapy. These included G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha, interleukin-1 beta, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4, interleukin-6 (IL-6), and tumor necrosis factor-alpha. Soluble interleukin-2 receptor (sIL-2R) was measured serially during rhG-CSF therapy. Lymphocyte subpopulations including CD2, CD3, CD4, CD8, CD19, CD20, and CD25 were also measured, rhG-CSF was administered once daily as a 30-min infusion. The patient was treated with increasing dose levels of 100, 200, 400, 800, and 1,600 micrograms/m2/day. The level of endogenous G-CSF was elevated to 334 pg/ml before treatment and GM-CSF, IL-2, IL-3, and IL-6 were slightly elevated. Clinically, he showed a moderate response to a high dose of rhG-CSF (1,600 micrograms/m2/day). Plasma levels of G-CSF markedly increased during therapy but plasma levels of other cytokines did not show significant changes during therapy and lymphocyte subpopulations did not significantly change. A drastic increase in sIL-2R expression was observed after rhG-CSF infusion and an increase in sIL-2R expression occurred even before a major increase in granulocyte counts. These results showed that a high dose rhG-CSF therapy may influence the cytokine network as judged by the increased sIL-2R expression.
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PMID:Cytokine profile during high-dose rhG-CSF therapy in severe congenital neutropenia. 750 1

We investigated the effect of interleukin-4 (IL-4) on human hematopoietic progenitors using low-density bone marrow cells from 29 hematologically normal donors. We found that IL-4 could either inhibit or stimulate cell growth, depending upon the other constituents of the culture medium. At concentrations ranging from 0.1 to 10.0 micrograms/ml, it significantly inhibited colony-forming units granulocyte-macrophage (CFU-GM) in the presence of either fetal calf serum alone, erythropoietin, leukocyte-conditioned medium prepared with phytohemagglutinin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), or stem cell factor (SCF), in a dose-dependent fashion. In contrast, IL-4 stimulated CFU-GM colony multiplication in the presence of granulocyte colony-stimulating factor (G-CSF). Similar but less significant inhibitory effects were exerted by IL-4 on burst-forming units-erythroid (BFU-E). The growth-suppressive effect of IL-4 was partially reversed by IL-1 beta, and to a lesser extent by IL-6. When tested by enzyme-linked immunosorbent assay (ELISA), IL-4 suppressed cellular IL-1 beta production, and, similar to IL-4, anti-IL-1 beta-neutralizing antibodies inhibited CFU-GM colony growth, suggesting that the inhibition of endogenous IL-1 beta is a factor in regulating the IL-4 effect. Furthermore, in the absence of exogenous growth factors, IL-4 inhibited CFU-GM colony growth when anti-G-CSF neutralizing antibodies were also present. Therefore, we tested the effect of IL-4 on G-CSF receptors and found that 6- or 24-h incubation of low-density marrow cells with 1.0 microgram/ml IL-4 resulted in up-regulation of G-CSF receptors. Taken together, these results suggest that IL-4 possesses a dual modulatory role in the hematopoietic system via interaction with various cytokines.
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PMID:Growth factors controlling interleukin-4 action on hematopoietic progenitors. 750 81

Hormones of the hematopoietin class mediate signal transduction by binding to specific transmembrane receptors. Structural data show that the human growth hormone (hGH) forms a complex with a homodimeric receptor and that hGH is a member of a class of hematopoietins possessing an antiparallel 4-alpha-helix bundle fold. Mutagenesis experiments suggest that electrostatic interactions may have an important influence on hormone-receptor recognition. In order to examine the specificity of hormone-receptor complexation, an analysis was made of the electrostatic potentials of hGH, interleukin-2 (IL-2), interleukin-4 (IL-4), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the hGH and IL-4 receptors. The binding surfaces of hGH and its receptor, and of IL-4 and its receptor, show complementary electrostatic potentials. The potentials of the hGH and its receptor display approximately 2-fold rotational symmetry because the receptor subunits are identical. In contrast, the potentials of GM-CSF and IL-2 lack such symmetry, consistent with their known high affinity for hetero-oligomeric receptors. Analysis of the electrostatic potentials supports a recently proposed hetero-oligomeric model for a high-affinity IL-4 receptor and suggests a possible new receptor binding mode for G-CSF; it also provides valuable information for guiding structural and mutagenesis studies of signal-transducing proteins and their receptors.
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PMID:Receptor binding properties of four-helix-bundle growth factors deduced from electrostatic analysis. 752 Jul 94

Interleukin-4 (IL-4) has distinct hematopoietic activities, primarily as a costimulant with other cytokines to enhance colony formation of hematopoietic progenitors. We investigated the influence of IL-4 on stromal cell-supported long-term cultures (LTCs) of normal human bone marrow. Addition of IL-4 to LTCs of unseparated bone marrow or highly enriched CD34+ cells resulted in a significant increase of myeloid progenitors in the nonadherent, as well as in the stromal cell-adherent cell populations. In contrast, the total cell number was not influenced by IL-4, suggesting a selective effect on primitive progenitor cells. Cord blood cells or CD34+ bone marrow cells were incubated with stem cell factor (SCF) and/or IL-4 in stromal cell-free cultures. In these experiments, a twofold to fivefold increase of myeloid progenitor cells was observed in the presence of SCF and IL-4 as compared with SCF alone. Preincubation of the stromal cell cultures with IL-4 resulted in an enhanced adherence of CD34+ cells to the stromal layer. Secretion of hematopoietic growth factors produced by the stromal cells, such as granulocyte-macrophage colony-stimulating factor (G-CSF), and IL-1, was inhibited by IL-4. Thus, the increase of hematopoietic progenitors in LTCs, as observed in the presence of IL-4, can be at least partially explained by a costimulation of SCF and IL-4 on primitive progenitor cells and by an enhancement of hematopoietic cells to stroma. The downregulation of CSFs by IL-4 might prevent the expansion of the mature hematopoietic cell compartment.
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PMID:Human interleukin-4 enhances stromal cell-dependent hematopoiesis: costimulation with stem cell factor. 752 23

Murine eosinophils express the low-affinity Fc gamma receptors recognized by the monoclonal antibody (mAb) 2.4G2, which are involved in the activation of these cells. We have studied the membrane and RNA expression of the low-affinity Fc gamma receptors on murine eosinophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), and interleukin-4 (IL-4). Flow cytometric analysis (FACS) of eosinophils incubated with GM-CSF and IFN-gamma showed an up-regulation on the expression of these receptors with a maximal effect at 24 hr. IL-4 failed to induce any positive or negative effect in these cells. To assess the pattern of expression of the low-affinity Fc gamma receptors on eosinophils, Northern blot analyses were carried out using specific cDNA probes encoding for the Fc gamma RII and Fc gamma RIII. Murine eosinophils constitutively express transcripts for Fc gamma RII and RIII. Incubation with GM-CSF from 3 to 12 hr produced a potent induction of the two transcripts studied (Fc gamma RII and RIII). IFN-gamma did not induce any important up-regulation of the two transcripts from 3 to 12 hr of incubation. By contrast, IL-4 produced a marked inhibition of both transcripts at 24 hr of incubation. Expression of the gamma-chain transcript which is associated with Fc gamma RIII has been detected on freshly isolated eosinophils. This study demonstrates a different regulation pattern of these receptors depending on the cytokine or growth factor used to stimulate murine eosinophils.
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PMID:Modulation of the Fc gamma RII and Fc gamma RIII induced by GM-CSF, IFN-gamma and IL-4 on murine eosinophils. 752 44


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