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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)

Tumor necrosis factor (TNF) is synthesized by macrophages exposed to endotoxin. It produces haemorrhagic necrosis of a variety of tumours in mice and is cytostatic or cytocidal against various transformed cell lines in vitro, but viability of normal human or rodent cells is unaffected. The role of TNF is unlikely to be restricted to the rejection of tumours. Colony-stimulating factors (CSFs) are required for survival, proliferation and differentiation of haematopoietic progenitor cells. The haematopoietic growth factor known as granulocyte-monocyte colony-stimulating factor (GM-CSF) has the ability to stimulate proliferation and differentiation of normal granulocyte-monocyte and eosinophil stem cells and enhance the proliferation of pluripotent, megakaryocyte and erythroid stem cells. In addition, GM-CSF stimulates a variety of functional activities in mature granulocytes and macrophages, for example inhibition of migration, phagocytosis of microbes, oxidative metabolism, and antibody-dependent cytotoxic killing of tumour cells. We show here that TNF markedly stimulates production of GM-CSF messenger RNA and protein in normal human lung fibroblasts and vascular endothelial cells, and in cells of several malignant tissues.
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PMID:Recombinant human TNF induces production of granulocyte-monocyte colony-stimulating factor. 348 88

Tumor necrosis factor type alpha (TNF-alpha) is produced by monocytes and has been purified, sequenced, and cloned from the HL-60 cell line. Soluble products of monocytes stimulate endothelial cells to release multilineage hematopoietic colony-stimulating activity. To determine whether TNF-alpha could stimulate endothelial cells to produce these activities, we added recombinant human TNF-alpha to cultured human umbilical vein endothelial cells. Untreated endothelial cell conditioned medium and TNF-alpha-stimulated endothelial cell conditioned medium were tested for hematopoietic colony stimulating activity in colony-forming assays in methylcellulose. TNF-alpha stimulated growth factor production by endothelial cells. Fifth-passage human endothelial cells and multiply-passaged bovine aortic endothelial cells responded similarly to first-passage endothelial cells, indicating that the action of TNF-alpha on endothelial cells is direct and not due to contaminating lymphocytes or monocytes present in the first-passage cultures. To investigate the molecular basis for these findings, polyadenylylated RNA was prepared from the TNF-alpha-stimulated endothelial cells and probed for granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mRNA. Granulocyte-macrophage colony-stimulating factor, but not granulocyte colony-stimulating factor, message was detected. This finding suggests that at least some of the hematopoietic colony-stimulating activity released by the TNF-alpha-stimulated endothelial cells is granulocyte-macrophage colony-stimulating factor. These results demonstrate that a purified monocyte product can stimulate endothelial cells to produce the multilineage growth factor granulocyte-macrophage colony-stimulating factor and extend the role of this immunoregulatory protein to the regulation of hematopoiesis in vitro.
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PMID:Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor. 348 39

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) improve the survival of lethally irradiated animals through production of hematopoietic growth factors. Exposure of fibroblasts to TNF (1000 U/ml) drastically increased granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA at 1 h and the level returned nearly to baseline by 24 h. Levels of GM-CSF RNA were less than basal level at 24 h after exposure to irradiation alone. In contrast, cells cultured with TNF (1 h) and then irradiated, had prominent expression of GM-CSF mRNA at 24 h. Transcriptional run-on analysis has shown that TNF stimulated the rate of GM-CSF transcription by > 10-fold in irradiated cells. Moreover, TNF stabilized GM-CSF mRNA at 24 h after irradiation; 4 increased from < 20 min in untreated cells to > 2 h in cells cultured initially with TNF and followed by irradiation. We repeated the same experiments with IL-1 and found that IL-1 had the same effects on accumulation, transcription, and stabilization of GM-CSF RNA. Our findings indicate that TNF and IL-1 synergize with irradiation in expression of GM-CSF gene in human fibroblasts; this increased expression occurs by enhancement of transcriptional rate and post-transcriptional stabilization of GM-CSF mRNA.
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PMID:Tumor necrosis factor and interleukin-1 synergize with irradiation in expression of GM-CSF gene in human fibroblasts. 763 Feb 3

Tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) primed human neutrophils for enhanced release of superoxide in time- and dose-dependent manners. The priming effects of these cytokines were detected at 3 min and maximal at 10 min of preincubation. The potency of the maximal effect was TNF > GM-CSF > G-CSF. Exposure of human neutrophils to TNF, GM-CSF and G-CSF resulted in tyrosine phosphorylation of a 42-kDa protein and intracellular alkalinization in a dose-dependent manner. The dose-response curves for triggering of tyrosine phosphorylation and intracellular alkalinization by each cytokine were similar to those for priming the cells. The potency of the maximal effect on tyrosine phosphorylation was TNF > GM-CSF > G-CSF, whereas that on intracellular alkalinization was GM-CSF > TNF > G-CSF. Tyrosine phosphorylation was detected at 3 min and maximal at 5-10 min after stimulation with each cytokine. Tyrosine phosphorylation induced by TNF declined at 20-40 min, whereas that induced by GM-CSF or G-CSF was maintained for at least 40 min. Intracellular alkalinization induced by each cytokine required a lag time of 3-5 min and was sustained for at least 40 min. Tyrosine phosphorylation preceded or occurred concomitantly with intracellular alkalinization and priming of the cells. These findings indicate that tyrosine phosphorylation and intracellular alkalinization are early events in human neutrophils stimulated by TNF, GM-CSF and G-CSF, and that these early events may, at least in part, mediate activation or priming of human neutrophils by these cytokines.
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PMID:Tyrosine phosphorylation and intracellular alkalinization are early events in human neutrophils stimulated by tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor. 767 88

Serum levels of soluble intercellular adhesion molecule-1, soluble interleukin-2 receptor, and cytokines such as interleukin-3, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor were examined in patients with oral disorders with 20 healthy persons used as control subjects. Patients studied included 30 with squamous cell carcinoma, 26 with oral lichen planus, 20 with recurrent aphthous ulcer, 19 with acute odontogenic bacterial infection, 16 with pseudomembranous candidiasis, and 16 with herpetic gingivostomatitis. Compared with levels in control subjects, detectable serum levels of interleukin-3 (> or = 10 pg/ml) existed more frequently in pseudomembranous candidiasis (13/16), acute odontogenic bacterial infection (14/19), and squamous cell carcinoma (24/30) and of granulocyte-macrophage colony-stimulating factor (> or = 4 pg/ml) more frequently in recurrent aphthous ulcer (15/20) and squamous cell carcinoma (21/30). These cytokine levels were increased with T stage of squamous cell carcinoma. About 20 pg/ml of interleukin-4 was detected in serum from one third to one fourth of patients with oral lichen planus, recurrent aphthous ulcer, and squamous cell carcinoma. Tumor necrosis factor-alpha was hardly detected in most patients except those with oral lichen planus and squamous cell carcinoma in which about one third of the patients had more than 40 pg/ml of tumor necrosis factor-alpha in serum. More than 10 pg/ml of interleukin-6 was frequently detected in all disorders, especially recurrent aphthous ulcer (18/20), pseudomembranous candidiasis (12/16), and acute odontogenic bacterial infection (17/19).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum cytokines, interleukin-2 receptor, and soluble intercellular adhesion molecule-1 in oral disorders. 789 9

Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion molecules, enhances cytokine production, and induces tissue factor procoagulant activity. In the present study, we have examined the relative roles of the two cell surface receptors for TNF-alpha (p55 and p75) on endothelial cells, using antibodies with both agonistic and antagonistic activities. We report that anti-p55 receptor agonistic antibody Htr-9 induces the expression of tissue factor antigen and the release of interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In contrast, there is very little or no activation of endothelial cell responses by an anti-p75 agonist. TNF-alpha-induced expression of tissue factor and adhesion molecules, and release of IL-8 and GM-CSF, are decreased by antibodies with antagonistic activities for either receptor, although the effect of anti-p55 antibodies is markedly greater than that of anti-p75 antibodies. The responses of endothelial cells to lymphotoxin/TNF-beta are significantly decreased by anti-p55 antagonists alone. Our data suggest that endothelial cell responses to TNF-alpha, such as expression of tissue factor and adhesion molecules for mononuclear cells, which may be important in the pathogenesis of atherosclerosis, are mediated predominantly, but not exclusively, by the p55 TNF receptor.
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PMID:Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells. 791 75

The pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins produced by liver epithelial cells. PTX3 was recently cloned as an interleukin-1 (IL-1)-inducible gene in endothelial cells, with structural similarities to pentraxins in the C-terminal half of the molecule. The present study was designed to investigate the expression of PTX3 in the human leukocyte populations. Human peripheral blood mononuclear cells exposed to lipopolysaccharide (LPS) or IL-1 beta expressed significant levels of PTX3 mRNA. Tumor necrosis factor-alpha (TNF-alpha) was a less-effective inducer of PTX3, whereas IL-6, monocyte chemotactic protein-1, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interferon-gamma were inactive. Among leukocytes, only monocytes exposed to inflammatory cytokines or LPS expressed the PTX3 transcript, which was undetectable in resting or stimulated polymorphonuclear cells, T or B lymphocytes, and natural killer cells. PTX3 mRNA was also inducible in in vitro monocyte-derived macrophages, in tumor-associated macrophages, and in the myelomonocytic cell lines HL60, U937, and THP1, but not in GFD8, with the latter possibly representative of earlier stages of myelomonocytic differentiation. T- and B-cell lines had no detectable PTX3. Inhibition of transcription by actinomycin D blocked induction of PTX3 in monocytes and nuclear run-on analysis showed that LPS induces the expression of the PTX3 gene at the transcriptional level in isolated monocytes. Cycloheximide had no effect on PTX3 induction in U937 cells, but was inhibitory on monocytes exposed to LPS or IL-1 beta. Monoclonal antibody against TNF and the IL-1 receptor antagonists did not inhibit induction of PTX3 in monocytes by LPS, thus excluding these cytokines as secondary stimulators of PTX3. IL-4, but not dexamethasone or transforming growth factor-beta, inhibited PTX3 expression in monocytes. Using a PTX3-specific antiserum, release of PTX3 protein was demonstrated for the first time in stimulated monocytes as well as in endothelial and fibroblastic cells. Thus, PTX3, unlike the classical pentraxins CRP and SAP, is expressed and released by cells of the monocyte-macrophage lineage exposed to inflammatory signals.
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PMID:Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. 794 2

Secretion of unique eosinophil granule constituents may play a role in allergic and parasitic reactions. Therefore we have investigated possible mechanisms for regulation of secretion in eosinophils. A hemolytic plaque assay and an enzyme-linked immunospot (ELISPOT) assay were developed for detection of secreted eosinophil cationic protein (ECP) from single adherent eosinophils. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced release of ECP in a dose-dependent fashion but 4-alpha-PMA, an analogue that does not activate protein kinase C, did not cause degranulation. Staurosporine and K252a, inhibitors of protein kinase C, decreased PMA-induced ECP secretion. Low concentrations of cytochalasin B enhanced PMA-induced secretion but high concentrations had an inhibitory effect. The calcium ionophores A23187 and ionomycin were weaker secretagogues than PMA. Tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-5, N-formylmethionyl-leucyl-phenylalanine, and lipopolysaccharide caused little or no degranulation in adherent eosinophils. Preincubation of eosinophils with antibodies to CD18, the common beta chain of leukocyte adhesion proteins, resulted in inhibition of PMA-induced ECP release from adherent cells. 1,2-Bis(O-aminophenyl)-ethane-ethane-N,N,N',N'-tetraacetic acid (BAPTA), an agent that acts intracellularly by chelation of calcium, also inhibited PMA-mediated ECP release. In conclusion, PMA induces release of ECP from single adherent eosinophils and the effect appears to be mediated via protein kinase C and, in contrast to that in neutrophils, to be dependent on CD11/CD18 leukocyte integrins.
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PMID:Phorbol ester-induced degranulation in adherent human eosinophil granulocytes is dependent on CD11/CD18 leukocyte integrins. 809 65

Cutaneous I-A+ Langerhans cells are the principal antigen-presenting cells within the epidermis, capable of both initiating and eliciting CD4-dependent immune reactions. We recently demonstrated that epidermal Langerhans cells can present tumor-associated antigens and thus may be important in cutaneous tumor immunity. Despite the ability of Langerhans cells to present tumor antigens, they generally fail to induce protective tumor immunity against growing tumors in situ. We therefore investigated whether locally produced cytokines may be able to down-regulate the presentation of tumor-associated antigens and alloantigen by epidermal antigen-presenting cells in primed as well as in unprimed systems in vivo and in vitro. Naive syngeneic mice could be successfully immunized against the spindle cell tumor S1509a by injecting them with granulocyte-macrophage colony-stimulating factor-exposed and tumor-associated antigen-pulsed epidermal cells three times at weekly intervals. Co-incubation of epidermal cells in granulocyte-macrophage colony-stimulating factor and interleukin-1 alpha inhibited tumor-antigen presentation by epidermal antigen-presenting cells in this system and also inhibited alloantigen presentation in the primary mixed epidermal cell-lymphocyte reaction. Tumor necrosis factor-alpha appeared to be a significant mediator of the inhibitory effect of interleukin-1 alpha on the ability of epidermal antigen-presenting cells to induce protective tumor immunity, because addition of anti-tumor necrosis factor-alpha antibody abrogated the observed effect of interleukin-1 alpha. However, the effects of interleukin-1 alpha and tumor necrosis factor-alpha differed with regard to presentation of tumor-associated antigens by epidermal antigen-presenting cells in a primed system. Whereas incubation of epidermal cells in interleukin-1 alpha before or after tumor antigen pulse inhibited their ability to elicit a delayed-type hypersensitivity response against S1509a tumor-associated antigens in tumor-immune mice, culture in tumor necrosis factor-alpha significantly enhanced delayed-type hypersensitivity. Again, these in vivo data corresponded well to similar results obtained in vitro using the secondary mixed epidermal cell-lymphocyte reaction. Incubation of epidermal cells in transforming growth factor-beta, which has been shown to down-regulate T-cell-mediated immune responses in other systems, did not suppress tumor immunity in our assays. Thus, interleukin-1 alpha may be an important regulator of Langerhans cell antigen-presenting function, having effects that are partially mediated via interleukin-1 alpha-induced up-regulation of tumor necrosis factor-alpha secretion within the skin.
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PMID:Interleukin 1 alpha but not transforming growth factor beta inhibits tumor antigen presentation by epidermal antigen-presenting cells. 828 13

Human fetal liver (FL) and neonatal cord blood (CB) granulocyte-monocyte colony-forming progenitor cells (GM-CFC) are unique in their physiological environment and in certain proliferative and differentiative capacities. Tumor necrosis factor (TNF) and interferon (IFN) may inhibit or stimulate the growth of human bone marrow GM-CFC in vitro. The effects of recombinant human (rh) TNF-alpha, rhIFN-alpha, and rhIFN-tau on recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF)-stimulated clonogenic cultures of day 7 GM-CFC from FL and umbilical CB were compared with rhGM-CSF-stimulated GM-CFC from normal human bone marrow (BM). We demonstrate that, in comparison to BM progenitor cells, GM-CFC from both FL and CB were highly resistant to growth inhibition by all three cytokines. Furthermore, clonogenic growth of progenitors from FL and CB was markedly potentiated by IFN-tau in GM-CSF-stimulated cultures and was stimulated by IFN-tau in the absence of GM-CSF. Depletion of potential accessory cells resulted in a marked stimulatory response of CB cells to TNF-alpha, in the presence of GM-CSF, while it did not alter the responses to IFN. The stimulatory effects of IFN-tau and TNF-alpha may be indirectly mediated, at least in part, through induction of increased GM-CSF production and increased GM-CSF receptor expression by fetal cells. Divergent responses of myelopoietic cells, derived from various hematopoietic compartments, to regulatory actions of cytokines may provide a basis for further understanding the role of the environment in maturation and differentiation of granulocytes and monocytes.
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PMID:Differential responses of fetal, neonatal, and adult myelopoietic progenitors to interferon and tumor necrosis factor. 829 33


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