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)

Since data on the ability of human mast cells to produce various cytokines are scanty, we examined the mRNA expression, its modulation and the resulting protein expression of a number of well-characterized cytokines, using semi-quantitative reverse transcription-polymerase chain reaction of cell extracts and enzyme-linked immunosorbent assays for analysis of cell supernatants. One million cells/ml of the human mast cell line HMC-1 were stimulated with 25 ng/ml phorbol myristate acetate (PMA), 5 x 10(-7) M calcium ionophore A 23187 (ionophore) or both stimuli combined for various time periods. Constitutive expression in unstimulated cells was found for interleukin-1 beta (IL-1 beta) -3, -4, -8, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta). Maximal mRNA up-regulation was observed by 2-4 hr, with a second peak for TNF-alpha at 24 hr. After a 4-hr stimulation, IL-13 expression was detectable as well, whereas for IL-12, only the p35 but not the p40 chain was found, and IL-2, -5, -7 and interferon-gamma (IFN-gamma) were not expressed at all. Large quantities of IL-8, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 were secreted time-dependently over a 72-hr period, with lower levels of IL-1 beta, -6, -10 and TGF-beta and no detectable IL-2, -4 and IFN-gamma protein. When IL-6 and IL-8 expression was compared in more detail, IL-6 mRNA was found to be up-regulated only with ionophore but not PMA, whereas both stimuli alone or combined increased IL-8 mRNA expression. Preincubation with cycloheximide inhibited IL-6 but not IL-8 transcription, and incubation of stimulated cells with actinomycin D stabilized IL-8 and also IL-6 mRNA. These data suggest a selective regulation of distinct cytokines in human mast cells at the transcriptional and post-transcriptional levels. Furthermore, the spectrum of cytokines produced by HMC-1 cells supports the well-recognized role of mast cells in immediate-type hypersensitivity reactions as well as their potential colony-stimulating and tissue-remodelling abilities.
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PMID:Comparative cytokine gene expression: regulation and release by human mast cells. 961 81

In the present study, we investigated the differentiation of human NK cells from bone marrow, cord blood and mobilized peripheral blood purified CD34+ stem cells using a potent culture system. Elutriated CD34+ stem cells were grown for several weeks in medium supplemented with stem cell factor (SCF) and IL-15 in the presence or absence of a murine stromal cell line (MS-5). Our data indicate that IL-15 induced the proliferation and maturation of highly positive CD56+ NK cells in both types of culture, although murine stromal cells slightly increased the proliferation of NK cells. NK cells differentiated in the presence of MS-5 were mostly CD56+ CD7 and a small subset expressed CD16. These in vitro differentiated CD56+ NK cells displayed cytolytic activity against the HLA class I- target K562. The CD56+ CD16+ subset also lysed NK-resistant Daudi cells. Neither of these NK subsets were shown to express Fas ligand. Total CD56+ cells expressed high amounts of transforming growth factor-beta and granulocyte-macrophage colony-stimulating factor, but no IFN-gamma. Investigation of NK receptor expression showed that most CD56+ cells expressed membrane CD94 and NKG2-A mRNA. PCR analysis revealed that p58 was also expressed in these cells. The role of CD94 in NK cell-mediated cytotoxicity was assessed on human HLA-B7-transfected murine L cells. While a low cytotoxic activity towards HLA-B7 cells was observed, the HLA-DR4 control cells were killed with high efficiency. These studies demonstrate that cytolytic and cytokine-producing NK cells may be derived from adult and fetal precursors by IL-15 and that these cells express a CD94 receptor which may influence their lytic potential.
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PMID:NK cells differentiated from bone marrow, cord blood and peripheral blood stem cells exhibit similar phenotype and functions. 964 81

We determined whether human lung fibroblasts (HLFs) might release mediators that are responsible for monocyte chemokinetic activity (MCA) constitutively. HLF supernatant fluids showed MCA in a time-dependent manner (P < 0.001). Checkerboard analysis of 24- and 72-h supernatant fluids showed that the activity was chemokinetic. Partial characterization of 24- and 72-h supernatant fluids revealed that the mediators released after 24 h were predominantly composed of lipid-soluble activity, and MCA was blocked by lipoxygenase inhibitors. The mediators released after 72 h were predominantly trypsin sensitive and blocked by cycloheximide. Molecular-sieve column chromatography identified four peaks of MCA. A polyclonal antibody to monocyte chemoattractant protein-1 (MCP-1) inhibited MCA by 20% after 24 h and by 40% after 72 h. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta (TGF-beta) antibodies attenuated MCA released after 72 h by 30 and 10%, respectively. These antibodies inhibited corresponding molecular-weight peaks separated by molecular-sieve column. The concentrations of MCP-1, GM-CSF, and TGF-beta were 4,698 +/- 242, 26.8 +/- 3.8, and 550 +/- 15 pg/ml, respectively. A leukotriene B4 (LTB4)-receptor antagonist attenuated the total MCA and the lowest molecular weight peak of MCA. The concentrations of LTB4 were 153.4 +/- 12.4 (24 h) and 212 +/- 16.6 (72 h) pg/ml. These findings suggest that HLFs may modulate the recruitment of monocytes into the lung by releasing MCP-1, GM-CSF, TGF-beta, and LTB4 constitutively.
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PMID:Human lung fibroblasts release chemokinetic activity for monocytes constitutively. 970 81

Muscle is an attractive target for gene therapy and for immunization with DNA vaccines and is also the target of immunological injury in myositis. It is important therefore to understand the immunologic capabilities of muscle cells themselves. In this study, we show that proinflammatory stimuli induce the expression of other cytokines such as IL-6, transforming growth factor-beta (TGF-beta), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by muscle cells themselves, as well as the up-regulation of human leucocyte antigen (HLA) class I, class II and intercellular adhesion molecule-1 (ICAM-1). Thus, muscle cells have an inherent ability to express and respond to a variety of cytokines and chemokines. The levels of HLA class I, class II and ICAM-1 in inflamed muscle may be affected by the secreted products of the stimulation.
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PMID:A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli. 973 70

Endotoxin tolerance, the down-regulation of a subset of endotoxin-driven responses after an initial exposure to endotoxin, may provide protection from the uncontrolled immunological activation of acute endotoxic shock. Recent data suggest, however, that the inhibition of monocyte/macrophage function associated with endotoxin tolerance can lead to an inability to respond appropriately to secondary infections in survivors of endotoxic shock. IL-12 production by antigen-presenting cells is central to the orchestration of both innate and acquired cell-mediated immune responses to many pathogens. IL-12 has also been shown to play an important role in pathological responses to endotoxin. We therefore examined the regulation of IL-12 during endotoxin tolerance. Priming doses of lipopolysaccharide ablate the IL-12 productive capacity of primary human monocytes. This suppression of IL-12 production is primarily transcriptional. Unlike the down-regulation of TNF-alpha under such conditions, the mechanism of IL-12 suppression during endotoxin tolerance is not dependent upon IL-10 or transforming growth factor-beta, nor is IL-12 production rescued by IFN-gamma or granulocyte-macrophage colony-stimulating factor. Of note, human dendritic cells also undergo endotoxin tolerance, with potent down-regulation of IL-12 production. Endotoxin tolerance-related suppression of IL-12 production provides a likely mechanism for the anergy seen during the immunological paralysis which follows septic shock.
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PMID:Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance. 980 81

Peripheral blood, bronchoalveolar lavage and sputum eosinophils of patients with asthma but not peripheral blood eosinophils from normal controls have been shown to express human leucocyte antigen (HLA)-DR on their cell surface. Cytokines implicated in the activation of eosinophils, such as interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), can up-regulate HLA-DR expression. However, little is known about antagonistic factors that might down-regulate HLA-DR expression on eosinophils. In this study we investigated whether transforming growth factor-beta (TGF-beta), which has been shown to reduce survival of activated eosinophils, can also modulate HLA-DR expression on eosinophils. For this purpose, isolated peripheral blood eosinophils were stimulated with IL-3 and GM-CSF for 24 h and HLA-DR expression was measured by flow cytometry. We found that while isolated eosinophils expressed low levels of surface HLA-DR, incubation with GM-CSF and IL-3 increased HLA-DR expression on eosinophils. TGF-beta alone did not change HLA-DR expression on isolated eosinophils. However, co-incubation of eosinophils with TGF-beta and either GM-CSF or IL-3 significantly decreased HLA-DR expression compared to eosinophils incubated with either GM-CSF or IL-3 alone and this was not reversed by addition of IL-5. This effect of TGF-beta on IL-3-induced HLA-DR expression was attenuated dose-dependently in the presence of monoclonal anti-TGF-beta antibodies. Our results suggest that TGF-beta can reduce cytokine-induced HLA-DR expression on eosinophils and could thus influence eosinophil activation.
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PMID:Inhibition of HLA-DR expression on activated human blood eosinophils by transforming growth factor-beta1. 987 2

The cytokines that regulate angiogenesis in normal and malignant prostate tissue are not well studied. Using an RT-PCR-based screen, we observed that cultured, low-passage normal human prostate epithelial cells (PrECs) express a variety of cytokines which have been shown to have angiogenic and/or endothelial cell-activating properties in various systems. These include vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Expression of VEGF, bFGF, GM-CSF, G-CSF, TGF-alpha and TNF-alpha in these cells was confirmed by immunohistochemistry. Culture medium conditioned by normal human PrECs for periods of up to 96 hr were found to contain VEGF, GM-CSF, G-CSF, IL-8, TGF-beta1 and TGF-beta2 but not TNF-alpha or bFGF, as determined by ELISA. Of these, VEGF was by far the most prominently expressed angiogenic cytokine (approx. 2,500 pg/ml conditioned medium at 96 hr vs. 30 to 100 pg/ml conditioned medium for the other cytokines). PrEC-conditioned medium induced an approximately 2-fold stimulation of [3H]-thymidine incorporation in cultured human umbilical cord endothelial cells (HUVECs) deprived of the endothelial growth factors VEGF and bFGF; this stimulation was abolished by neutralizing antibodies directed against VEGF but not bFGF, IL-8, GM-CSF or TNF-alpha. VEGF expression by PrECs was not markedly altered by administration or deprivation of other angiogenic cytokines for which these cells have receptors, suggesting that there is not a hierarchy of cytokines controlling its expression; however, retinoic acid, a component of PrEC growth medium, was found to modestly suppress VEGF at physiological concentrations (0.1 ng/ml). These data suggest that normal PrECs express a variety of angiogenic cytokines, most prominently VEGF, to recruit a supporting vasculature, even in culture. Our data also suggest that the ability of malignant PrECs to stimulate angiogenesis may be intrinsic and does not need to be acquired during oncogenesis.
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PMID:Expression of multiple angiogenic cytokines in cultured normal human prostate epithelial cells: predominance of vascular endothelial growth factor. 1007 20

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression.
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PMID:Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. 1009 49

Bone marrow stroma produces positive and negative growth regulators which constitute the hematopoietic microenvironment. As many tumors metastasize to the bones, these regulators may also influence tumor growth. Hematopoietic cytokines may indeed exert both positive and negative effect on tumor growth. We report that, when mixed with tumor cells. adherent bone marrow cells inhibit primary tumor growth and metastases formation in mice transplanted with Lewis lung carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not exert any influence. The tumor inhibition was apparently due to soluble factor(s) released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent bone marrow cells exerted a significant antiproliferative effect which was increased by previous culture of the bone marrow cells with granulocyte-macrophage colony-stimulating factor but not with macrophage colony-stimulating factor. Neither neutralizing antibodies against tumor necrosis factor-alpha, transforming growth factor-beta or interferon alpha/beta nor addition of Escherichia coli lipopolysaccharide to generate inflammatory cytokines could affect the antiproliferative effect of bone marrow stromal cells. The bone marrow stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth regulator.
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PMID:Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. 1035 34

It has been reported that tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 induce the release of monocyte chemotactic factors (MCF), including chemokines, from A549 cells, an alveolar type II cell line. However, the relative contribution of these chemokines to MCF is still uncertain. In the present study, the relative contribution of various chemokines released from A549 cells acting as MCF upon stimulation by TNF-alpha and IL-1alpha, was evaluated. TNF-alpha and IL-1alpha induced the release of MCF in a dose- and time-dependent manner (p<0.001). The release of MCF was inhibited by cycloheximide and lipoxygenase inhibitors. Molecular sieve column chromatography revealed multiple peaks of MCF (near 60 kDa, 25-22 kDa, 15-13 kDa, 8 kDa, and 400 Da). Leukotriene B4 (LTB4) receptor-antagonists inhibited MCF by 50% after 24 h and 30% after 72 h. Monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-beta, "regulated on activation, normal T-cells, expressed and secreted" (RANTES), and granulocyte-macrophage colony- stimulating factor (GM-CSF) were released significantly in response to IL-1alpha and TNF-alpha, and antibodies to MCP-1, GM-CSF, and RANTES inhibited MCF activity by 40, 5 and 20% after 24 h, and by 50, 20, and 10% after 72 h, respectively. Each antibody or LTB4 receptor-antagonist inhibited the corresponding column chromatography-separated molecular weight peak of MCF. These data suggest that A549 cells release monocyte chemoattractant protein-1 as the predominant monocyte chemotactic factor rather than granulocyte-macrophage colony-stimulating factor, RANTES, and transforming growth factor-beta, and that leukotriene B4 is constitutively released as a monocyte chemotactic factor.
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PMID:Monocyte chemotactic factors released from type II pneumocyte-like cells in response to TNF-alpha and IL-1alpha. 1036 47


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