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

The fps/fes proto-oncogene encodes a cytoplasmic protein tyrosine kinase that is thought to participate in signaling pathways involving members of the cytokine receptor superfamily, including those for erythropoietin, granulocyte-macrophage colony-stimulating factor, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and interleukins 3, 4, 6, and 11. Expression of fps/fes has been detected in hematopoietic cells, vascular endothelial cells, and cell types arising from all three germ layers during early development. Here, we describe fps/fes expression in developing and adult tissues from normal mice or from transgenic animals overexpressing wild-type or activated mutant fps/fes alleles. The highest levels of fps/fes expression were seen in angioblasts of early yolk sac blood islands, chondrocytes, vascular endothelial cells, neuronal cells, and several epithelial cell types, including those of the choroid plexus and the uterus. Fps/Fes protein was concentrated in the perinuclear region of cultured neuronal, myeloid, epithelial, and vascular endothelial cells, and a chimeric Fps/Fes-green fluorescence protein colocalized with gamma-adaptin, a marker for the trans-Golgi apparatus. These observations suggest the involvement of Fps/Fes in vesicle transport processes in cells with prominent secretory functions.
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PMID:The fps/fes tyrosine kinase is expressed in myeloid, vascular endothelial, epithelial, and neuronal cells and is localized in the trans-golgi network. 880 11

Macrophage colony-stimulating factor (M-CSF) is essential for murine osteoclast formation and its role in human hematopoiesis in vitro is not fully defined. Therefore, we have investigated the effect of M-CSF on the formation of human osteoclasts in vitro. M-CSF was found to induce substantial bone resorption and osteoclast formation in a dose-responsive and time-dependent manner above that induced by 1,25 dihydroxyvitamin D3 (1,25 vitamin D3) in cultures of human bone marrow (BM) stromal cells sedimented onto devitalized bone. By day 14 there was a mean of approximately 50% of the surfaces of the bone slices resorbed compared with only 6% in cultures treated with 1,25 vitamin D3 alone. Osteoclasts were identified as 23c6+ cells (an antibody that recognizes the vitronectin receptor), 87.5% of which coexpressed the calcitonin receptor. The number of 23c6+ cells correlated strongly with bone resorption spatially, and in a dose-responsive and time-dependent manner; the correlation coefficient in cultures treated with 1,25 vitamin D3 alone was 0.856 and those treated with both M-CSF and 1,25 vitamin D3 was 0.880. Granulocyte-macrophage colony-stimulating factor, IL-1 beta, IL-3, IL-6, tumor necrosis factor-alpha, transforming growth factor-beta, leukemia inhibitory factor, and IL-11 did not increase bone resorption above that in 1,25 vitamin D3-treated cultures. We also found that 1,25 vitamin D3 increased, to a minor but significant degree, both bone resorption and the concentration of M-CSF in the culture supernatants above that in vehicle-treated cultures, indicating that M-CSF is present in our BM cultures, but that there is insufficient to induce substantial osteoclast formation. These results define a critical role for M-CSF in the formation of human osteoclasts.
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PMID:Macrophage colony-stimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures. 883 45

Based on anatomic and developmental findings characterizing hematopoietic cells in close approximation with endosteal cells, we have begun an analysis of osteoblast/hematopoietic cell interactions. We explore here the functional interdependence between these two cell types from the standpoint of de novo cytokine secretion. We determined that, over a 96-hour period, CD34+ bone marrow cells had no significant effect on osteoblast secretion of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or transforming growth factor-beta1, but in some experiments minor increases in leukemia inhibitory factor levels were observed. However, when CD34+ bone marrow cells were cocultured in direct contact with osteoblasts, a 222% +/- 55% (range, 153% to 288%) augmentation in interleukin-6 (IL-6) synthesis was observed. The accumulation of IL-6 protein was most rapid during the initial 24-hour period, accounting for nearly 55% of the total IL-6 produced by osteoblasts in the absence of blood cells and 77% of the total in the presence of the CD34+ cells. Cell-to-cell contact does not appear to be required for this activity, as determined by coculturing the two cell types separated by porous micromembranes. The identity of the soluble activity produced by the CD34+ cells remains unknown, but is not likely due to IL-1beta or tumor necrosis factor-alpha, as determined with neutralizing antibodies. To our knowledge, these data represent the first demonstration that early hematopoietic cells induce the production of molecules required for the function of normal bone marrow microenvironments, in this case through the induction of hematopoietic cytokine (IL-6) secretion by osteoblasts.
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PMID:Augmented production of interleukin-6 by normal human osteoblasts in response to CD34+ hematopoietic bone marrow cells in vitro. 902 38

Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo regulation of hematopoiesis under conditions of steady state or stress, providing insights into the physiological roles of hematopoietic growth factors and their importance in the pathogenesis of disease. As mediators of pathological processes, hematopoietic growth factors may be targets for antagonist therapy in some diseases. Exogenous hematopoietic growth factors may also be useful therapeutically to augment physiological responses, so understanding hematopoietic growth factor regulation and serum levels may assist the development of specific therapies. Hematopoietic growth factor levels may also serve as tumor markers and assist prognostication or monitoring during the clinical course of an illness. The growth factors of particular interest include the four classic colony-stimulating factors: granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and multi-colony-stimulating factor, also known as interleukin-3. Other cytokines with hematopoietic growth factor activity include interleukin-1, interleukin-6, interleukin-11, stem cell factor (also known as Steel factor or mast cell growth factor), and leukemia inhibitory factor.
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PMID:Measurement and clinical significance of circulating hematopoietic growth factor levels. 937 Dec 87

Cytokines manifest their function through regulation of gene expression. We searched for immediate-early cytokine responsive genes by the mRNA differential display technique using interleukin-3 (IL-3)-dependent OTT-1 cells, and have isolated a novel cDNA which encodes 210 amino acids and shows 87% amino acid identity to human SNAP-23 (synaptosomal-associated protein of 23 kD). The message for this protein (mouse SNAP-23) was induced in OTT-1 cells by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5. The experiment using C-terminal deletion mutants of the common beta subunit (betac) of IL-3/GM-CSF/IL-5 receptors showed that expression of SNAP-23 was associated with the Ras-Raf-MAPK pathway, but not with the JAK-STAT pathway. Moreover, SNAP-23 was induced in response to a wide variety of cytokines, including IL-2, IL-3, IL-5, IL-10, stem cell factor, G-CSF, GM-CSF, leukemia inhibitory factor, and erythropoietin. Constitutive expression of SNAP-23 was seen in various tissues, including heart, lung, kidney, liver, spleen, and small intestine. Possible involvement of SNAP-23 in cytokine signal transduction is discussed.
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PMID:Induction of synaptosomal-associated protein-23 kD (SNAP-23) by various cytokines. 963 8

Marrow stromal cells of patients treated by autologous bone marrow transplantation (ABMT) for malignancies have been assessed for their ability to secrete granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), transforming growth factor beta1 (TGFbeta1) and macrophage inflammatory protein-1alpha. (MIP-1alpha). Long-term marrow cultures were established from 10 patients prior to and 3 months after ABMT, from 7 patients 1 yr after ABMT and from 11 controls. Cytokines in culture supernatants of stromal layers (SL) were evaluated by enzyme-linked immunosorbent assay (ELISA). Significant differences between patient groups and controls were apparent in baseline production of GM-CSF, SCF, MIP-1alpha and TGFbeta1. After IL-1beta addition in cultures, G-CSF production was reduced in pretransplant and post-transplant patients compared to controls. The production of TGFbeta1, LIF, IL-6 and more particularly SCF were reduced in post-transplant patients, while elevated levels of GM-CSF and MIP-1alpha were observed in these patients only when the values were corrected for the number of cells growing in the SL. These results indicate a prolonged stromal defect in growth factor production following ABMT for the early-stage acting cytokines IL-6, LIF and SCF as well as for G-CSF, but not for GM-CSF, while the production of the 2 inhibitors shows different pathways.
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PMID:Cytokines released in vitro by stromal cells from autologous bone marrow transplant patients with lymphoid malignancy. 971 21

It was recently reported that transgenic expression in the liver of truncated human Met renders hepatocytes constitutively resistant to apoptosis and reproducibly permits their immortalization. The derived stable cell lines (MMH from Met murine hepatocyte) are highly differentiated and nontransformed. In this report, the capacity of MMHs to support in vitro hematopoiesis is characterized. By reverse-transcription polymerase chain reaction, the expression by MMHs of cytokines involved in the survival and self-renewal of early progenitor cells (stem cell factor and FLT3 ligand) as well as those acting at different stages of progenitor differentiation (interleukin [IL] 1beta, IL-3, leukemia inhibitory factor, IL-6, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and thrombopoietin) was shown. A ribonuclease protection assay further substantiated the presence of at least six cytokine transcripts in MMH lines. Cocultures between MMH layers and progenitor-enriched fetal liver hematopoietic cells resulted in a 40-fold to 80-fold expansion of total hematopoietic cells and in a 2.5-fold expansion of clonogenic progenitors after 1 to 2 weeks. Hematopoiesis was maintained for up to 6 weeks with formation of typical cobblestone cell areas and continuous differentiation of precursor into cells at various degrees of maturation. At 5 weeks of coculture, clonogenic progenitors were maintained at 20% of the input level in coculture with embryonic-derived hepatocytes, showing the ability of hepatocyte feeder layer to support survival and possibly self-renewal of clonogenic progenitors. Therefore, the data emphasize a direct role of the hepatocyte in sustaining hematopoietic cell proliferation and differentiation.
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PMID:Hematopoietic support and cytokine expression of murine-stable hepatocyte cell lines (MMH). 982 30

Macrophage-derived cytokines and chemokines are involved at multiple steps of immune and inflammatory responses, and the transcriptional factor NF-kappaB appears to play a pivotal role in their coordinated upregulation. The anti-inflammatory agents salicylates have been proposed to act in part by inhibiting NF-kappaB. We have therefore studied the effects of sodium salicylate on lipopolysaccharide (LPS)-induced kappaB-binding activity and on cytokine and chemokine gene expression in the RAW264.7 murine macrophage cell line and compared them to those of an established NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). PDTC (100 microM) completely abrogated LPS-induced kappaB-binding activity and also profoundly inhibited the induction of interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-10, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and MCP-1 and, to a lesser extent, leukemia inhibitory factor, RANTES, and IL-1Ra. In contrast, sodium salicylate (15 to 20 mM) had no effect on NF-kappaB activation but, nevertheless, suppressed several LPS-induced cytokine and chemokine genes to a degree similar to that obtained with PDTC. However, compared to PDTC, sodium salicylate caused significantly less inhibition of IL-1Ra and IL-10 gene expression after LPS stimulation. Neither LPS-induced MIP-1alpha, MIP-1beta, nor MIP-2 was significantly affected by PDTC or sodium salicylate, demonstrating that NF-kappaB is dispensable for the transcriptional regulation of these genes by LPS. In summary, these results suggest that both NF-kappaB-dependent and NF-kappaB-independent pathways are necessary for the induction by LPS of a complex cytokine and chemokine response. In the RAW264.7 macrophage cell line, suprapharmacological concentrations of sodium salicylate exert a potent inhibitory effect on LPS-induced cytokine gene induction but appear to accomplish this by interfering with NF-kappaB-independent pathways of activation.
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PMID:Inhibition of cytokine gene expression by sodium salicylate in a macrophage cell line through an NF-kappaB-independent mechanism. 1039 64

We have developed a stromal-based in vitro culture system that facilitates ex vivo expansion of transplantable CD34(+) thy-1(+) cells using long-term hematopoietic reconstitution in severe combined immunodeficient-human (SCID-hu) mice as an in vivo assay for transplantable human hematopoietic stem cells (HSCs). The addition of leukemia inhibitory factor (LIF) to purified CD34(+) thy-1(+) cells on AC6.21 stroma, a murine bone marrow-derived stromal cell line, caused expansion of cells with CD34(+) thy-1(+) phenotype. Addition of other cytokines, including interleukin-3 (IL-3), IL-6, granulocyte-macrophage colony-stimulating factor, and stem cell factor, to LIF in the cultures caused a 150-fold expansion of cells retaining the CD34(+) thy-1(+) phenotype. The ex vivo-expanded CD34(+) thy-1(+) cells gave rise to multilineage differentiation, including myeloid, T, and B cells, when transplanted into SCID-hu mice. Both murine LIF (cannot bind to human LIF receptor) and human LIF caused expansion of human CD34(+) thy-1(+) cells in vitro, suggesting action through the murine stroma. Furthermore, another human HSC candidate, CD34(+) CD38(-) cells, shows a similar pattern of proliferative response. This suggests that ex vivo expansion of transplantable human stem cells under this in vitro culture system is a general phenomenon and not just specific for CD34(+) thy-1(+) cells.
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PMID:Long-term ex vivo maintenance and expansion of transplantable human hematopoietic stem cells. 1096 Feb 42

The present study was designed to determine cytokines produced by primary human bronchial epithelial cells (HBECs) exposed to ambient air pollution particles (EHC-93). Cytokine messenger RNA (mRNA) was measured using a ribonuclease protection assay and cytokine protein production by enzyme-linked immunosorbent assay. Primary HBECs were freshly isolated from operated lung, cultured to confluence, and exposed to 10 to 500 microg/ml of a suspension of ambient particulate matter with a diameter of less than 10 microm (PM(10)) for 2, 8, and 24 h. The mRNA levels of leukemia inhibitory factor (LIF), granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1alpha, and IL-8 were increased after exposure to PM(10), and this increase was dose-dependent between 100 (P < 0.05) and 500 (P < 0.05) microg/ml of PM(10) exposure. The concentrations of LIF, GM-CSF, IL-1beta, and IL-8 protein measured in the supernatant collected at 24 h increased in a dose- dependent manner and were significantly higher than those in the control nonexposed cells. The soluble fraction of the PM(10) (100 microg/ml) did not increase these cytokine mRNA levels compared with control values and were significantly lower compared with HBECs exposed to 100 microg/ml of PM(10) (LIF, IL-8, and IL-1beta; P < 0.05), except for GM-CSF mRNA (P = not significant). We conclude that primary HBECs exposed to ambient PM(10) produce proinflammatory mediators that contribute to the local and systemic inflammatory response, and we speculate that these mediators may have a role in the pathogenesis of cardiopulmonary disease associated with particulate air pollution.
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PMID:Particulate matter induces cytokine expression in human bronchial epithelial cells. 1158 2


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