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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)

Interleukin-4 (IL-4) regulates the growth of B cells. When combined with colony-stimulating factors (CSFs) and selected cytokines, IL-4 has a synergistic effect on the clonal growth of bone marrow cells. Recently, we have shown that IL-1 alpha and lipopolysaccharide induce expression of the granulocyte-macrophage CSF (GM-CSF) gene in murine B-cell lines. In the present study, we show that IL-4 inhibits the production of GM-CSF in the IL-1 alpha-stimulated murine B-cell line M12.4.1. IL-4 did not change the transcription rate of the GM-CSF gene, and caused only a slight decrease in cytoplasmic GM-CSF messenger RNA (mRNA) half-life in cells treated with IL-1 alpha. PCR analysis of nuclear RNA with probes specific for GM-CSF intron sequences suggests that IL-1 alpha enhances accumulation of nuclear precursor RNA and that decreased GM-CSF expression after IL-4 treatment is mainly due to intranuclear destabilization of the primary transcript. Under the same experimental conditions, IL-4 did not affect expression of the IL-4 receptor mRNA and did increase the mRNA concentration of the low-affinity receptor for IgE (Fc epsilon RII). These data suggest that the suppressive effect of IL-4 is specific for GM-CSF mRNA expression, and thus provide evidence for an additional role of IL-4 in the regulation of GM-CSF expression in B cells.
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PMID:Interleukin-4 inhibits interleukin-1 alpha-induced granulocyte-macrophage colony-stimulating factor gene expression in a murine B-lymphocyte cell line via downregulation of RNA precursor. 159 64

We investigated the effect of recombinant human interleukin-4 (rhIL-4) on the in vitro growth of human leukemia cells in liquid culture and 3H-thymidine incorporation and found inhibitory effects on the growth of leukemic cells from patients with Ph1-positive acute lymphoblastic leukemia (Ph1 ALL) and three Ph1 ALL cell lines. However, no inhibitory effects were seen in Ph1-positive leukemic cell lines derived from patients with chronic myelogenous leukemia in blast crisis and various types of Ph1-negative leukemia cells, including B-lineage leukemia cells. In a flow cytometry assay of IL-4 receptor (IL-4R), all three Ph1-positive ALL cell lines showed the presence of IL-4R on their cell surfaces, and the IL-4-dependent inhibition on the growth of Ph1-positive ALL cells was abrogated by the addition of either monoclonal or polyclonal antibodies against rhIL-4. Other cytokines, including IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and IL-6, showed no inhibitory effects on the growth of Ph1-ALL cells, but tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-alpha, -beta, and -gamma displayed slight inhibitory effects in a high concentration. The growth inhibition induced by rhIL-4 in the Ph1-positive ALL cells was not abrogated by the addition of antibodies against either IFN-gamma or TNF-alpha. Furthermore, these cells showed no significant production of IFN-alpha, -beta, or -gamma or TNF-alpha after exposure to rhIL-4, thus indicating that the growth inhibition of Ph1-positive ALL cells by rhIL-4 is not associated with IL-4-stimulating production of these factors. rhIL-4 caused significant inhibition of the tyrosine kinase activity in these Ph1-positive ALL cells, similar to Herbimycin A, an inhibitor of tyrosine kinase that inhibited the tyrosine kinase activity in these cells. Our finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibilities for patients with Ph1-positive ALL.
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PMID:Inhibitory effect of interleukin-4 on the in vitro growth of Ph1-positive acute lymphoblastic leukemia cells. 188 23

Interleukin-4 (IL-4) is a T-cell-derived cytokine that regulates induction of proliferation of resting B cells and acts on various other immunocompetent cells, such as monocytes/macrophages and mast cells, as well as hematopoietic progenitor cells. On hematopoietic progenitor cells, cooperation with another cytokine (such as granulocyte-macrophage colony-stimulating factor [GM-CSF], G-CSF, IL-3, or IL-6) is required to render the cells responsive to IL-4. The present study was undertaken to determine if such an interaction entails induction of IL-4 receptor (IL-4R) expression. Using the murine myeloid leukemia M1 cell line and mature, bone marrow (BM)-derived macrophages, we investigated whether IL-4R expression can be induced during differentiation. We detected no high-affinity IL-4R on the surface of either cell, but with exposure to IL-6 a significant induction of IL-4R was measured on both cell types by fluorescence-activated cell sorter analysis. This increase in IL-4R was first noted 6 hours after exposure of the cells to IL-6 and continued to increase up to 48 hours. By RNase protection analysis we found that the expression of IL-4R mRNA also appeared within 6 hours, continuing to increase up to 48 hours. Nuclear run-on assays showed that this increase in steady-state level of IL-4R mRNA results from a transcriptional activation of the IL-4R gene. These data suggest that regulation of IL-4R expression by IL-6 is under transcriptional control.
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PMID:Regulation of interleukin-4 receptors on murine myeloid progenitor cells by interleukin-6. 191 57

In this report a method for the affinity purification and radiolabeling of recombinant mouse interleukin (IL)-4 is described. It is shown on the basis of several criteria that IL-4 retains full biologic activity after radioiodination and can therefore be used as a valid model for measuring the binding characteristics of native IL-4. By using Scatchard plot analysis of equilibrium binding data, it is demonstrated that 125I-IL-4 binds to a high affinity cell surface receptor which is expressed by both hemopoietic and nonhemopoietic cells. The dissociation constant for 125I-IL-4 (Kd = 20 to 60 pM) corresponds to the concentration of IL-4 which gives 50% biologic activity (i.e., 10 to 30 pM). Binding of 125I-IL-4 is rapid (t1/2 of 2 min), whereas dissociation occurs at a slow rate (t1/2 approximately 4 hr). The IL-4 receptor shows a high degree of specificity. Whereas unlabeled mouse IL-4 competed with mouse 125I-IL-4 in an equimolar fashion for binding to IL-4 receptors, several other lymphokines, including mouse IL-2, IL-3, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and human IL-1, IL-2, and IL-4 were unable to inhibit, even at molar excesses of 400 to 800-fold. At 37 degrees C, 125I-IL-4 is rapidly internalized (approximately 200 molecules/cell/min) by HT-2 cells, with at least 85% of cell surface receptors being functional in this respect. Receptors for IL-4 were found to be expressed by subclasses of T and B cells, mast cells, macrophages, and by cells of the myeloid and erythroid lineages. This wide distribution of receptor expression closely matches the known spectrum of biologic activities of IL-4, including proliferation and/or differentiation of T and B cells, mast cells and granulocytes, and induction of macrophage antigen-presenting capacity. IL-4 receptors were also found on a variety of nonhemopoietic cells such as cloned stromal cell lines from the bone marrow, spleen, thymus, and brain, and on muscle, brain, melanoma, fibroblast, and liver cells. Indeed, only 5 of more than 90 cell types tested have undetectable numbers of IL-4 receptors. The biologic effects of IL-4 on nonhemopoietic cells have not yet been reported and await elucidation.
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PMID:Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. 296 13

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

Leukemic cells from a patient with chronic myelocytic leukemia (CML) basophilic crisis were examined in an in vitro clonogenic assay using recombinant human hematopoietic growth factors to elucidate the proliferative and differentiative behaviors. More than 90% of the leukemic cells showed the morphologic characteristics of basophils and were positive for CD11b and CD13. The phenotype of the leukemic cells was different from that of mast cells. In the clonogenic assay using various recombinant growth factors, the leukemic cells were responsive to interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not to granulocyte-CSF (G-CSF), erythropoietin (Epo), or IL-4. IL-5 showed synergistic effects on colony formations induced by both IL-3 and GM-CSF. Transcripts of the GM-CSF receptor alpha chain gene were detected in the leukemic cells, but transcripts of the IL-4 receptor gene were not. Furthermore, c-kit and IL-7 receptor genes were expressed in the leukemic cells. Our results suggest that the differentiation pathway of basophils is different from that of mast cells, even though the receptor gene for stem cell factor (c-kit) was expressed on the basophilic leukemic cells, as it was on mast cells.
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PMID:Cellular characteristics of chronic myelocytic leukemia basophilic crisis cells: phenotype, responsiveness to and receptor gene expression for various kinds of growth factors and cytokines. 767 84

Interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor, and IL-5 receptors (IL-3R, GMR, and IL-5R) are composed of the alpha chain specific to each and the common beta chain, and both the alpha and beta subunits are members of the cytokine receptor superfamily. We previously showed that the high-affinity human GMR reconstituted by cotransfecting the alpha and beta chain cDNA clones transduces signals in response to hGM-CSF to activate transcription of c-fos, c-jun, and c-myc proto-oncogenes in mouse proB cell line BA/F3 or in mouse fibroblast NIH3T3 cells. These results indicated that molecules, such as tyrosine kinase, unique to hematopoietic cells are not essential to transduce signals. In this study, the function of the alpha subunit of GMR was compared with those of IL-3R and IL-5R by cotransfecting human cDNAs encoding the alpha subunit of IL-3R or IL-5R and the common beta subunit into BA/F3 or NIH3T3 cells. We found that the reconstituted human IL-3R, in response to hIL-3, transduced signals to activate transcription of c-fos promoter and induced DNA synthesis in both types of cells in a manner similar to hGMR. Likewise, hIL-5 activates c-fos promoter in transfected NIH3T3 cells expressing hIL-5R. These results indicated that the alpha subunits of IL-3R and IL-5R have properties similar to those of the GMR alpha subunit. In contrast, transfected human IL-4 receptor (hIL-4R) cDNA, which weakly activated c-fos promoter and induced DNA synthesis in BA/F3 cells, failed to elicit these activities in NIH3T3 cells in response to hIL-4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of early response genes and cell proliferation by human interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 receptors: comparison with human interleukin-4 receptor signaling. 808 68

Semi-quantitative, polymerase chain reaction (PCR) is used to uncover the patterns of cytokine transcription in the mouse thymus from day 14 to day 20 of gestation, a time period which includes many of the important events in thymic ontogeny. Interleukin 4 (IL-4), IL-7 and interferon gamma (IFN-gamma) mRNA is abundant from fetal day (Fd) 14-16, corresponding with the period of rapid proliferation of immature thymocytes in vivo. As the level of mRNA for these cytokines diminishes, the induction and increased expression of IL-3 and IL-2 occurs. The transcription of these cytokines correlates temporally with the period of proliferation-dependent phenotypic differentiation between Fd 16 and 20. The thymic epithelium (TE)-derived cytokines including IL-1alpha, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) begin to be transcribed between Fd 14-15 and show peak mRNA abundance from Fd 16-20. IL-5, tumour necrosis factor alpha (TNF-alpha) and LT (lymphotoxin or TNF-beta) constitute a fourth group of cytokines, along with the IL-4 receptor (IL-4R), which are transcribed at an even level throughout the fetal period. The IL-2 receptor beta chain (IL-2Rbeta) and IL-10 show abundant mRNA from Fd 14-20 and have a peak level of mRNA content on Fd 16. Taken together, these studies uncover complex, overlapping patterns of cytokine gene expression. The mRNA abundance and pattern of expression of each cytokine or cytokine receptor may indicate the relative contribution that it makes to different stages of fetal thymic ontogeny.
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PMID:Semi-quantitative polymerase chain reaction analysis of cytokine and cytokine receptor gene expression during thymic ontogeny. 934 2

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1beta that was abrogated by a neutralizing antibody to the IL-4 receptor alpha (IL-4Ralpha)-chain but not to the IL-2 receptor gamma (IL-2Rgamma)-chain. Expression of cell surface IL-4 receptors and IL-4Ralpha in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1beta. Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1beta. However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1beta, was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1beta is mediated by a constitutive cell surface IL-4Ralpha and the activation of multiple intracellular pathways.
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PMID:Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. 1195 62

The presence of interleukin-4 (IL-4) during the generation of dendritic cells (DC) from precursor cells results in measurable increases of IL-12 in supernatants but IL-4 secretion has not been reported. However, DC have IL-4 receptors and are able to make IL-4. We therefore sought evidence for autocrine effects of IL-4 on DC. IL-4 gene expression was low in DC generated from bone-marrow stem cells in the presence of granulocyte-macrophage colony-stimulating factor but was up-regulated by exposure of the developing DC to IL-4. Exposure to IL-4 also induced intracellular IL-4 production in DC. The intracellular IL-4 induced in the presence of IL-4 was increased following further DC maturation with tumour necrosis factor-alpha. By contrast, in supernatants of DC, IL-4 was rarely detected and only at late culture periods. However, after exposure of DC to IL-4, cell-bound IL-4 was detected transiently, which suggested binding and internalization of the cytokine. Binding via IL-4 receptor-alpha was indicated from phosphorylation of the signal transducer and activator of transcription (STAT) protein 6, which is known to mediate IL-4 function. Cytokine persisting within the supernatants of the cells may therefore be unrepresentative of the actual production and function of IL-4 in the cells; IL-4 may be produced in DC in response to exposure to IL-4 but may then be lost from the supernatants during cell binding and activation of the cells.
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PMID:Interleukin-4 can induce interleukin-4 production in dendritic cells. 1642 63


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