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)

CD95 (Fas, APO-1) is a cell surface receptor expressed on many cells including eosinophils which mediates apoptosis when ligated by agonistic antibodies or its natural ligand FasL. Since inhibition of apoptosis may play an important role in controlling tissue eosinophilia, we investigated the expression of CD95 on purified peripheral blood eosinophils from normal donors. Freshly isolated eosinophils expressed CD95 on the cell surface as well as CD95-specific mRNA at low levels which did not change during 24-h culture. Incubation of eosinophils with IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) did not modulate the basal expression of CD95. IFN-gamma as well as TNF-alpha, however, induced a significant, dose- and time-dependent increase in CD95 mRNA and cell surface expression as measured by reverse transcription-PCR and flow cytometry. Co-stimulation with IFN-gamma and TNF-alpha had synergistic effects on the CD95 surface expression on eosinophils. Addition of IL-3, IL-5 or GM-CSF to IFN-gamma- and TNF-alpha-stimulated eosinophils caused in a reduction of CD95 expression. Functional activity for CD95 following incubation with IFN-gamma and TNF-alpha was demonstrated by increased apoptosis in response to cross-linking with FasL. From these data, we conclude that IFN-gamma and TNF-alpha can up-regulate cell surface expression of CD95 on eosinophils, which leads to an increased susceptibility of eosinophils to Fas-mediated apoptosis. Thus, our results suggest that receptors involved in eosinophil apoptosis can be regulated by antagonistic cytokines.
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PMID:Differential regulation of CD95 (Fas/APO-1) expression in human blood eosinophils. 969 73

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

GM-CSF is a cytokine with pleiotropic biological activities and is increasingly used in clinical trials. The present study demonstrates the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) to induce elevation of interleukin-10 (IL-10) mRNA and protein production in the monocytic cell line U937. As shown by a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), IL-10 mRNA increases up to 10 times when stimulated with rGM-CSF (100 U/ml) compared to nonstimulated control cells. Maximal IL-10 mRNA expression occurs at 6 h and remains high for 2 h. Thereafter IL-10 mRNA is downregulated and reaches basal level at approximately 24 h. IL-10 protein was measured by ELISA. The protein yield is dose-dependent on the rGM-CSF concentration. Combined stimulation of U937 cells with both GM-CSF and TNF-alpha results in an additive elevation of the IL-10 protein yield. Application of a neutralising antibody against TNF-alpha revealed that GM-CSF induces IL-10 expression independently from TNF-alpha. By using a luciferase reporter gene it was shown that rGM-CSF enhances IL-10 promoter activity 2-3-fold in a transient transfection assay.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor triggers interleukin-10 expression in the monocytic cell line U937. 979 52

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

The cytokines are (glyco)proteins secreted by lymphoid and non-lymphoid cells which modulate several biological responses including the ovarian function. Interleukin (IL)-1 and tumour necrosis factor (TNF)-alpha suppress 17beta-estradiol (E2) and progesterone release from granulosa and luteal cells in vitro. TNF-alpha affects negatively folliculogenesis and ovarian maturation. Additional in vivo evidence for a role of this macrophage-derived cytokine came from our recent observation that women with infertility due to immunological causes have elevated intrafollicular fluid levels of TNF-alpha and decreased levels of E2 compared to women with a tubal factor of infertility. Because the macrophages are a primary component of the intrafollicular compartment, the present study was undertaken to evaluate whether other macrophage-derived cytokines are also released in the human follicular fluid. To accomplish this, we measured the levels of IL-1beta, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the follicular fluids of two groups of infertile women undergoing to an in vitro fertilization program. The first group of women had a significant titre of anti-spermatozoon antibodies in the serum and/or the mucus as the only cause of infertility, whilst the second group of women was infertile because of non patent fallopian tubes. Intrafollicular cytokines levels were measured by solid-phase ELISA and steroid concentrations by radioimmunoassay. Whilst IL-1beta, IL-6, IL-10, and GLM-CSF were all measurable in the follicular fluid of both groups of women, the levels of IL-6 were found to be significantly more elevated and those of GM-CSF lower in patients with infertility due to immunological causes as compared to those with tubal infertility. The former had also decreased intrafollicular E2 levels and increased progesterone concentrations. No difference was seen in the follicular fluid levels of testosterone and androstenedione. In conclusion, several macrophage-derived cytokines are present in the follicular fluids of infertile women. Patients with infertility due to immunological causes had higher levels of IL-6 and lower concentrations of GM-CSF as compared to patient with a tubal factor of infertility. We speculate that this abnormal cytokine profile may contribute to the altered intrafollicular steroid milieu.
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PMID:Macrophage-derived cytokines in the follicular fluids of women with infertility due to immunological causes. Elevated levels of interleukin 6 and low levels of granulocyte-macrophage colony-stimulating factor. 981 36

The capacity of dendritic cells (DC) to initiate immune responses is dependent on their specialized migratory and tissue homing properties. Chemotaxis and transendothelial migration (TEM) of DC were studied in vitro. Immature DC were generated by culture of human monocytes in granulocyte-macrophage colony-stimulating factor and IL-4. These cells exhibited potent chemotaxis and TEM responses to the CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, and monocyte chemotactic protein-3, and weak responses to the CC chemokine MIP-3beta and the CXC chemokine stromal cell-derived factor (SDF)-1alpha. Maturation of DC induced by culture in lipopolysaccharide, TNF-alpha or IL-1beta reduced or abolished responses to the former CC chemokines but markedly enhanced responses to MIP-3beta and SDF-1alpha. This correlated with changes in chemokine receptor expression: CCR5 expression was reduced while CXCR4 expression was enhanced. These findings suggest two stages for regulation of DC migration in which one set of chemokines may regulate recruitment into or within tissues, and another egress from the tissues.
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PMID:Dendritic cell chemotaxis and transendothelial migration are induced by distinct chemokines and are regulated on maturation. 986 47

The physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has influence over osteoclastogenesis and myelopoiesis, but the regulational mechanism is not well-defined. In this report, formation of osteoclast-like (OCL) cells from primitive myeloid colony-forming cells (PM-CFC) as mediated by 1,25(OH)2D3 was examined. Our results present in this report clearly show that 1,25(OH)2D3 dose-dependently stimulated OCL cell formation when added to suspension cultures of individually replated PM-CFC colonies. Marrow cells were plated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or the human bladder carcinoma cell line 5637 conditioned medium (5637 CM) as the source of colony-stimulating activity. The 1,25(OH)2D3 effect of osteoclast differentiation was associated with a concomitant decrease in clonogenic growth of myelopoietic progenitors in response to colony-stimulating activity. Secondly, the effect of adding the known stimulator of hematopoiesis, interleukin-1beta (IL-1beta) and/or 1,25(OH)2D3 on human myeloid colony growth was assessed. IL-1beta enhanced the formation of primitive myeloid colonies in response to GM-CSF by 160%. On the other hand, 1,25(OH)2D3 dose-dependently inhibited both GM-CSF- and 5637 CM-driven myeloid colony formation by as much as 90% at 100 nM. Addition of IL-1beta to GM-CSF-stimulated cultures dampened the inhibitory effect of 1,25(OH)2D3. The inhibition of myeloid clonogenic growth by 1,25(OH)2D3 was almost abolished (89%) by simultaneously adding anti-tumor necrosis factor-alpha monoclonal antibody (anti-TNF-alpha MoAb) to the culture medium. These results collectively suggest divergent roles for 1,25(OH)2D3 in osteoclastogenesis and myelopoiesis, promoting the differentiation of OCL cells from primitive myeloid cells but inhibiting the proliferation of later myeloid progenitor cells. This inhibition of myeloid progenitors may be mediated by TNF-alpha.
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PMID:Divergent regulation of 1,25-dihydroxyvitamin D3 on human bone marrow osteoclastogenesis and myelopoiesis. 1002 20

The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may facilitate this process. First, we investigated whether CD34(+) stem/progenitor cells express gelatinases A (MMP-2) and/or B (MMP-9) and whether growth factors and cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], stem cell factor [SCF], macrophage colony-stimulating factor [M-CSF], interleukin-3 [IL-3], IL-6, IL-8, and tumor necrosis factor-alpha [TNF-alpha]) are able to modulate their expression. Next, we examined the transmigration of these stem/progenitor cells through reconstituted basement membrane (Matrigel) and its modulation by growth factors and cytokines. CD34(+) cells were obtained from steady-state bone marrow and peripheral blood (from leukapheresis products collected either in steady-state hematopoiesis or after mobilization with G-CSF plus chemotherapy or G-CSF alone). We found that peripheral blood CD34(+) cells, regardless of whether they were mobilized or not, strongly expressed both gelatinases (MMP-2 and MMP-9) in contrast to steady-state bone marrow CD34(+) cells, which did not. However, all the growth factors and cytokines tested could induce MMP-2 and MMP-9 secretion by the latter cells. Moreover, the stimulatory effects of G-CSF and SCF on both MMP-2 and MMP-9 secretion were found to be significantly higher in CD34(+) cells isolated from bone marrow than in those from peripheral blood. In addition TNF-alpha, GM-CSF, and IL-6 increased the secretion of a partially active form of MMP-2. Basal transmigration of bone marrow CD34(+) cells through Matrigel was lower than that of peripheral blood CD34(+) cells (P <.0001), but growth factors and cytokines increased it by 50% to 150%. Positive correlations were established between expression of gelatinases and CD34(+) cell migration (r >.9). The stimulatory effect of G-CSF was significantly greater on the migration of CD34(+) cells from bone marrow than on those from peripheral blood (P =.004). Moreover, CD34(+) cell migration was reduced to approximately 50% by antibodies to MMP-2 and MMP-9, tissue inhibitors of metalloproteinases (rhTIMP-1 and -2), and o-phenanthroline. TNF-alpha-induced gelatinase secretion and migration of CD34(+) cells and of clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], and colony-forming unit-megakaryocyte [CFU-MK]) were dose-dependent. Therefore, this study demonstrated that CD34(+) cells that are circulating in peripheral blood express both MMP-2 and MMP-9 and transmigrate through Matrigel. In contrast, CD34(+) cells from steady-state bone marrow acquire similar properties after exposure to growth factors and cytokines, which upregulate expression of gelatinases and transmigration of these cells when they enter the bloodstream. Hence, we suggest that growth factors and cytokines induce release of stem/progenitor cells from bone marrow into peripheral blood during mobilization, as well as during steady-state hematopoiesis, by signaling through gelatinase pathways.
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PMID:Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane. 1023 90

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

We reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma line Pam 212 exhibit an elevation in constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF-kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappaB. We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells. The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappaB as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF-kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression. These data indicate that activation of NF-kappaB contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in squamous cell carcinoma.
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PMID:The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. 1041 16


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