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 effect of recombinant human (rh) interleukin-4 (rIL-4) on human blood BFU-E was investigated using two populations of cells: platelet-depleted low-density mononuclear cells (FH,Pl- cells), as unpurified cells, and highly purified BFU-E. When FH,Pl- cells were cultured with rh-erythropoietin (rEp), rIL-4 inhibited BFU-E growth in a dose-dependent manner. However, the addition of rIL-4 did not affect rh-interleukin-3 (rIL-3) supported BFU-E growth. Limiting dilution analysis (LDA) of FH,Pl- cells showed that rIL-4 suppressed endogenous production of burst-promoting activity (BPA) by accessory cells. Highly purified BFU-E were used as target cells to measure BPA in the conditioned medium (CM) that was prepared by FH,Pl- cells. When 100 purified BFU-E were cultured in 0.5 ml clots with 20% (vol/vol) of the CM, the number of BFU-E colonies was increased by the CM. The increase was significantly reduced by the addition of the CM prepared in the presence of rIL-4, but anti-IL-4 blocked the effect of rIL-4. The concentration of IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CM was determined by an enzyme-linked immunoadsorbent assay (ELISA). The spontaneous production of GM-CSF but not IL-3 was detected, and this was significantly decreased in the presence of rIL-4. Anti-GM-CSF but not anti-IL-3 inhibited CM supported BFU-E growth, indicating that the main BPA in the CM is GM-CSF and that rIL-4 suppresses the spontaneous production of GM-CSF by accessory cells. From these studies, we conclude that rIL-4 has a unique mechanism as a negative regulator on erythropoiesis through the inhibition of BPA production by blood mononuclear accessory cells.
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PMID:Recombinant human interleukin-4 inhibits the production of granulocyte-macrophage colony stimulating factor by blood mononuclear cells. 791 61

We employed alginate-entrapped cells secreting recombinant murine interleukin-4 (IL-4) to study the effect of IL-4 on hematopoietic cells of normal mice. The most dramatic effect was registered in an increase in the neutrophils and to a lesser extent the monocytes. A small increase in the CD4+, CD8+ and B220+ populations was also observed. Serum IgE levels also increased dramatically. All of these increases could be specifically inhibited with anti-IL-4. Antibodies to granulocyte-macrophage colony-stimulating factor, IL-3 and IL-5 could also inhibit some IL-4-mediated actions suggesting an interplay between these cytokines in vivo.
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PMID:Potential interaction of interleukin-4 with endogenous cytokines in vivo. 794 14

Acute myelogenous leukemia (AML) cells express CD23 surface antigen after in vitro treatment with various cytokines, including interleukin-4 (IL-4) and interferon gamma. Subsequent ligation of CD23 by specific monoclonal antibody (MoAb) induces substantial morphologic and functional modifications in these cells. In the present study, we investigated the role of CD23 in the proliferation and the maturation of leukemic cells from AML patients or the U937 cell line. CD23+ cell treatment with CD23 MoAb inhibited the proliferation of leukemic cells. This correlated with their terminal differentiation after 7 to 9 days incubation because they (1) definitively lost their growth capacity; (2) adhered to culture flasks and became monocyte/macrophage-like; and (3) expressed mature monocyte markers including nonspecific esterases. Intracellular mechanism of this antitumoral effect was then analyzed in U937 cells. Induction of high-density surface CD23 expression by IL-4 or granulocyte-macrophage colony-stimulating factor coincided with a transient decrease of U937 cell proliferation. CD23 ligation during this low-proliferative phase induced a rapid activation of L-arginine-dependent pathway and the intracellular accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). Induction of these early messengers was followed by the activation of nuclear factor-kB transcription factor and the modulation of proto-oncogene expression by U937 cells. Whereas U937 cell treatment with IL-4 decreased c-fos/c-jun expression, CD23 MoAb reinduced c-fos/c-jun and promoted the expression of cell maturation-associated proto-oncogenes junB and c-fms, during the first 24 hours. Both IL-4 and CD23 MoAb downregulated the expression of c-myb. CD23 ligation also induced the production of TNF alpha by U937 cells. Inhibitors of cAMP and nitric oxide reversed CD23-mediated modification in U937 cells. These data evidence the ability of CD23 surface antigen to mediate terminal differentiation of early leukemic myelomonocytic cells.
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PMID:Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. 794 82

We recently found that microglia, brain macrophages, express interleukin-4 (IL-4) receptor mRNA in vitro. Since IL-4 exhibits a variety of functions on the cells of monocyte-macrophage lineage, we examined the effects of IL-4 on the functions of microglia. Recombinant IL-4 induced the proliferation of microglia in a dose- and time-dependent manner as determined by MTT colorimetric assay, [3H]thymidine uptake and bromodeoxyuridine (BrdU) incorporation. IL-4 also synergistically enhanced the proliferation of microglia with such colony-stimulating factors as IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). It also increased acid phosphatase activity and superoxide anion formation by these cells. Despite these positive effects on proliferation and activation, IL-4 suppressed the IFN gamma-induced class II MHC antigen expression in these cells. Since these effects of recombinant IL-4 were inhibited by the addition of monoclonal antibody against IL-4 receptors, the effects of IL-4 on microglia appear to be a specific function via IL-4 receptors. Although microglia and astrocytes produce a variety of immunoregulatory cytokines, neither cell produced IL-4 as determined by bioassay or detection of IL-4 mRNA by RT-PCR method. Thus, the exogenous IL-4 may contribute to the accumulation of microglia in or around inflammatory lesions in the central nervous system, and may be involved in the regulatory mechanisms of microglia.
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PMID:Interleukin-4 induces proliferation and activation of microglia but suppresses their induction of class II major histocompatibility complex antigen expression. 807 35

A synthetic segment (110-127) of the carboxyl terminus of recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF) was used to generate a rabbit polyclonal antibody (345-6), which recognized both peptide and full-length Escherichia coli-derived rh-GM-CSF in a direct enzyme-linked immunosorbent assay. Antibody 345-6 was shown to antagonize the binding of 125I-labeled rh-GM-CSF to its receptor on the KG-1 cell line and to inhibit human GM-CSF-dependent proliferation of the AML-193 cell line. The purified IgG fraction of neutralizing antibody 345-6 was used as immunogen to obtain sheep anti-serum 1418. Antibody 1418 recognized antibody 345-6 on direct enzyme-linked immunosorbent assay but did not recognize rh-GM-CSF or the peptide 110-127 to which antibody 345-6 was raised. Antiserum 1418, as well as a purified IgG fraction of this serum, inhibited both rh-GM-CSF-stimulated cell proliferation and 125I-labeled rh-GM-CSF receptor binding but not 125I-labeled recombinant human interleukin-4 receptor binding. The anti-idiotypic antibody response derived from the anti-(110-127) antibody strongly suggests that the carboxyl-terminal region of rh-GM-CSF may be directly involved in the receptor-ligand interaction of this protein. The high affinity receptor consists of two different components (GM-R alpha beta) a cytokine-specific alpha-subunit and a beta-subunit that is shared by human GM-CSF, interleukin-3, and interleukin-5. In an effort to localize the epitope of antibody 1418 to either GMR alpha or GMR beta, several cell lines containing high, low, or both high and low affinity receptors were examined. Each was specifically and completely inhibited by antibody 1418. Interleukin-3-dependent cell proliferation of the AML-193 cell line was found to be unaffected by the antibody 1418. Thus, the carboxyl-terminal region of rh-GM-CSF is likely to be involved in the interaction of the ligand with the alpha-subunit of the high affinity receptor.
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PMID:A role for the carboxyl terminus of human granulocyte-macrophage colony-stimulating factor in the binding of ligand to the alpha-subunit of the high affinity receptor. 811 89

This study examines the distribution of intraepithelial dendritic cells in eight atopic patients with symptomatic asthma and their ability to induce activation of autologous T lymphocytes in vitro. All subjects were sensitized to Dermatophagoides pteronyssinus. The incubation of asthmatic epithelial cells and dendritic cells with autologous resting CD4-positive T cells and purified extracts of D pteronyssinus induced T cell activation and release of high levels of interleukin-4 (IL-4) and interleukin-5 (IL-5). The antigen-presenting activity of dendritic cells was potentiated by epithelial cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF), since an antibody against GM-CSF reduced it. Circulating monocytes of the two groups of donors were equally effective in promoting selective activation of IL-4- and IL-5-producing T cells. Thus, an interaction between dendritic cells and allergens may favor local activation of CD4-positive T cells with Th2-like function in atopic asthmatic subjects, thereby promoting the expression of the disease.
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PMID:Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. 813 11

The effect of nedocromil sodium (NES) on human immunoglobulin (Ig) isotypes, IgG subclasses and IgA subclasses was studied. NES inhibited IgM and IgA1 production from human lymphoblastoid B-cell lines CBL and GM-1056, respectively, in a dose-dependent fashion. This inhibition was not due to decreased cell growth as cell proliferation was not affected by NES and cell viability was always greater than 98%. Of the various cytokines tested, interleukin-4 (IL-4) reduced the NES-induced inhibition of Ig production, whereas other cytokines, including IL-1 beta, IL-2, IL-3, IL-5, IL-6, interferon-alpha (IFN-alpha), IFN-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo) failed to do so. The reducing effect of IL-4 was blocked by anti-IL-4 antibody but not by control IgG. Moreover, IFN-alpha and IFN-gamma, but not GM-CSF, overcame the reducing effect of IL-4. NES also inhibited production of IgM, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2 by tonsillar B cells stimulated with Staphylococcus aureus Cowan strain I (SAC) and IL-6 without affecting proliferation. This inhibition was reduced by IL-4 specifically. These results indicate that in addition to its anti-allergic function, NES may act as a B-cell regulatory reagent.
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PMID:Nedocromil sodium acts directly on human B cells to inhibit immunoglobulin production without affecting cell growth. 813 19

Endothelial cells (EC) may regulate both local and systemic aspects of inflammation through the synthesis of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-6 (IL-6). EC are known to synthesize these cytokines in response to interleukin-1 (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). In this paper, we illustrate the effect of interleukin-4 (IL-4) in reducing the synthesis of GM-CSF by EC stimulated with IL-1 alpha, TNF-alpha, or LPS. This is compared with the previously reported strong synergy between IL-4 and IL-1 alpha, TNF-alpha, or LPS in the synthesis of IL-6 by EC. No clear effect of IL-4 was seen in the synthesis of G-CSF or M-CSF. The range of concentrations of IL-4 at which these effects were seen was identical for both reduced GM-CSF synthesis and increased IL-6 synthesis. The effect of IL-4 on IL-6 synthesis was seen by 4 h of treatment, while that on GM-CSF was apparent between 4 and 8 h. It is suggested that these contrasting effects of IL-4 may reflect a biological role for this cytokine in the regulation of leukocytosis and the acute phase response.
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PMID:Contrasting effects of interleukin-4 on colony-stimulating factor and interleukin-6 synthesis by vascular endothelial cells. 832 81

Cytokine-activation pathways in mast cells are supposed to play a significant role in host defense mechanisms and allergic reactions. Interleukin-4 (IL-4) is a well-characterized regulator of growth and function of mast cells. The human mast cell line HMC-1 was established from a patient suffering from mast cell leukemia and was shown to expose IL-4 binding sites. In the present study, the effects of recombinant human (rh) IL-4 and other rh cytokines (IL-2, IL-3, IL-6, IL-8) on expression of cytokine mRNA in HMC-1 cells were examined by Northern blot analysis using oligonucleotide probes. Tumor necrosis factor alpha (TNF-alpha) and IL-1 beta transcripts were found to be expressed constitutively in HMC-1 cells, whereas transcripts for IL-3, IL-4, IL-5, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) could not be detected. Of all cytokines tested, rhIL-4 was found to down-regulate IL-1 beta mRNA expression and formation of immunoreactive IL-1 beta protein in HMC-1 cells. The effect of IL-4 on IL-1 beta gene product expression was time- and dose-dependent (maximum effects obtained with 100 U/mL of rhIL-4). No effect of IL-4 on expression of TNF-alpha mRNA in HMC-1 cells was observed. These results raise the possibility that human mast cells are a source of both TNF-alpha and IL-1 beta. Furthermore, our study provides evidence that IL-4 regulates IL-1 beta gene product expression in HMC-1 cells. The HMC-1 cell line should be a useful tool for studying cytokine activation pathways in human mast cells.
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PMID:Tumor necrosis factor alpha and interleukin-1 beta mRNA expression in HMC-1 cells: differential regulation of gene product expression by recombinant interleukin-4. 833 Jun 51

Crystal and NMR structures of helical cytokines--interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-2 (IL-2)--have been compared. Root mean square deviations in the C alpha coordinates for the conserved regions of the helices were 1-2 A between different cytokines, about twice the differences observed for independently determined crystal and solution structures of IL-4. Considerable similarity in amino acid sequence in the areas expected to interact with the receptors was detected, and the available mutagenesis data for these cytokines were correlated with structure conservation. Models of cytokine-receptor interactions were postulated for IL-4 based on its structure as well as on the published structure of human growth hormone interacting with its receptors (de Vos, A.M., Ultsch, M., & Kossiakoff, A.A., 1992, Science 255, 306-312). Patches of positively charged residues on the surfaces of helices C and D of IL-4 may be responsible for the interactions with the negatively charged residues found in the complementary parts of the IL-4 receptors.
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PMID:Hematopoietic cytokines: similarities and differences in the structures, with implications for receptor binding. 840 Dec 23


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