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)

Previous experiments have revealed the expression of tumor necrosis factor alpha (TNF-alpha) transcripts in all murine bone marrow-derived macrophage colonies isolated from days 5 through 9 of differentiation in vitro. These results implicated a role for TNF-alpha gene expression during macrophage differentiation. Antisense oligomers to the initiation region of the TNF-alpha message were used to inhibit its expression, thus allowing the role of TNF-alpha gene expression in controlling the differentiation of macrophages to be determined. Results showed that TNF-alpha regulated the proliferation of macrophages during differentiation. Cells isolated on day 3 were exclusively vulnerable to the effects of blocking TNF-alpha gene expression, displaying a 30% increase in proliferation over control cells or sense oligomer-treated cells. Thus, in the absence of TNF-alpha gene expression, cells maintained proliferation instead of undergoing terminal differentiation. Exogenous TNF-alpha was capable of rescuing day 3 antisense-treated cells, therefore maintaining normal levels of proliferation. In contrast, blocking interleukin 1 beta gene expression by antisense oligonucleotide treatment had no effect on proliferation. Addition of exogenous recombinant murine or human TNF-alpha decreased the total cell number 25-50% regardless of whether cells were grown in medium containing colony-stimulating factor 1 (CSF-1) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These results suggested that exogenous TNF-alpha suppressed proliferation of early hematopoietic progenitors, whereas endogenous TNF-alpha regulated proliferation of macrophage progenitors. The number of differentiated, adherent macrophages on day 5 of differentiation in vitro was increased by TNF-alpha treatment of GM-CSF-induced macrophages but was suppressed in CSF-1-induced macrophages. These findings suggest that distinct TNF receptor expression and/or signaling is induced in differentiating macrophages stimulated with either growth factor.
 ...
PMID:Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. 850 31

Tumor necrosis factor (TNF)-alpha and TNF-beta have multiple effects on human acute myeloid leukemia (AML) cells in vitro, including (1) synergistic stimulation of proliferation with interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and upregulation of interleukin-3 (IL-3) and GM-CSF receptors; (2) inhibition of granulocyte-CSF (G-CSF)-induced growth and rapid downmodulation of G-CSF receptors; and (3) induction of autocrine growth. Recently, two distinct TNF receptors (TNF-Rs), TNF-R(p55) and TNF-R(p75), have been identified. In this study, we show that both receptor types may be expressed by AML blasts. It has been investigated whether the different effects of TNF on AML blasts can be explained by differential activation of the distinct TNF-R structures. For this purpose, we used the monoclonal antibodies HTR-1 and HTR-9, specifically recognizing TNF-R(p55), and UTR-1, specific for TNF-R(p75). TNF-(alpha and -beta) mediated synergistic activation with IL-3/GM-CSF, upregulation of IL-3/GM-CSF receptors, inhibition of G-CSF-induced growth, and rapid downmodulation of G-CSF receptors exclusively result from activation of TNF-R(p55). In certain cases in which TNF-alpha, rather than TNF-beta, induces AML growth through an autocrine mechanism, both TNF-R(p55) and (p75) are involved. These data indicate that the variety of TNF responses observed in AML can only be partially explained by differential activation of the TNF-R(p55) and (p75) structures, and that TNF-R(p55) on AML blasts can transduce both positive (synergism with IL-3/GM-CSF) and negative regulatory signals (inhibition of G-CSF-induced proliferation) following TNF activation.
 ...
PMID:Involvement of tumor necrosis factor (TNF) receptors p55 and p75 in TNF responses of acute myeloid leukemia blasts in vitro. 138 4

Tumor necrosis factor alpha (TNF alpha) has previously been reported to have both inhibitory and stimulatory effects on hematopoietic progenitor cells. Specifically, TNF alpha has been proposed to stimulate early hematopoiesis in humans. In the present study we show that TNF alpha, in a dose-dependent fashion, can potently inhibit the growth of primitive high proliferative potential colony-forming cells (HPP-CFCs) stimulated by multiple cytokine combinations. Using agonistic antibodies to the p55 and p75 TNF receptors or TNF alpha mutants specific for either of the two TNF receptors, we show that both receptors can mediate this inhibition. In contrast, the potent stimulation of interleukin-3 (IL-3) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) induced HPP-CFC colony formation observed at low concentrations of TNF alpha (2 ng/mL) was only a p55-mediated event. Moreover, the stimulatory effects of TNF alpha on GM-CSF or IL-3-induced colony formation, as well as the inhibition of G-CSF-induced colony growth, were also exclusively signaled through the p55 TNF receptor. Taken together, our results suggest that the inhibitory effects of TNF alpha on primitive bone marrow progenitor cells are mediated through both p55 and p75 TNF receptors, whereas the p55 receptor exclusively mediates the bidirectional effects on more mature, single factor-responsive bone marrow progenitor cells as well as stimulation of IL-3 plus GM-CSF-induced HPP-CFC colony growth.
 ...
PMID:Bifunctional effects of tumor necrosis factor alpha (TNF alpha) on the growth of mature and primitive human hematopoietic progenitor cells: involvement of p55 and p75 TNF receptors. 751 2

Intravenous administration of endotoxin into humans causes transient fever, alteration in the number of circulating neutrophils, and transient release into plasma of cytokines, cytokine antagonists, and other cellular products. The release can be temporally differentiated, and the extent of release is dose-dependent. By 1 h after endotoxin challenge, levels of tumor necrosis factor (TNF)-alpha and soluble TNF receptor increase; interleukin (IL)-6 and IL-8 increase by 1.5 h, and IL-1 receptor antagonist, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and lactoferrin increase by 2 h. Increased G-CSF is temporally associated with neutrophilia and the appearance of band neutrophils. Increased plasma lactoferrin and altered neutrophil surface antigen expression suggest that intravascular activation of neutrophils has occurred. The level of soluble E-selectin (sE-sel), an adhesion molecule released from endothelial cells, is elevated at 4 h and remains elevated at 24 h. sE-sel levels increase with higher doses of endotoxin at 4, 6, and 24 h.
 ...
PMID:Increased circulating cytokines, cytokine antagonists, and E-selectin after intravenous administration of endotoxin in humans. 752 50

An immunohistochemical technique was used to examine whether there was a colocalization of cytokine-specific receptors with cytokine-expressing cells. We have previously shown that there is extensive cytokine production and secretion in the rectal mucosa in shigellosis (interleukin 1 alpha [IL-1 alpha], IL-1 beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha [TNF-alpha], TNF-beta, gamma interferon, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta [TGF-beta]) (R. Raqib, A. A. Lindberg, B. Wretlind, P. K. Bardhan, U. Andersson, and J. Andersson, Infect. Immun. 63:289-296, 1995; R. Raqib, B. Wretlind, J. Andersson, and A. A. Lindberg, J. Infect. Dis. 171:376-384, 1995). Kinetics for receptor expression was compared with that for cytokine synthesis in the inflamed rectal mucosa from Shigella-infected patients during acute (2 to 6 days after onset of diarrhea) and convalescent (30 to 40 days after onset) stages. Quantification of receptor expression was assessed by computer-assisted analysis of video microscopic images. A selective down-regulation of the receptors for gamma interferon, tumor necrosis factor (TNF receptor [TNFR] type I), IL-1 (IL-1 receptor [IL-1R] types I and type II), IL-3, IL-4, and TGF-beta (TGF-beta receptor type I) was observed at the onset of the disease, with a gradual reappearance during the convalescent stage. However, IL-2R, IL-6R, granulocyte-macrophage colony-stimulating factor receptor, TNFR type II, and TGF-beta receptor type II showed no change in expression during the study period and were comparable to controls. Cytokine receptors were predominantly located to the epithelial layer of the mucosal surface and crypts, with variable expression patterns in the lamina propria. A time-dependent kinetic curve was seen for the soluble IL-2R (sIL-2R), sIL-6R, and sTNFR types I and type II shed in stool at the acute stage similar to that observed for cytokine secretion in stool but at four- to six-times-lower concentration. In contrast, soluble receptor levels in plasma were 100-fold higher than the cytokine levels. The results suggest a dissociation in immune regulation between cytokine production and cytokine receptor expression. The down-regulation of the receptors in acute shigellosis was probably a consequence of cytokine-induced internalization and shedding of the receptors during signal transduction as well as due to programmed regulatory roles played by cytokines and the bacterial antigens.
 ...
PMID:Down-regulation of gamma interferon, tumor necrosis factor type I, interleukin 1 (IL-1) type I, IL-3, IL-4, and transforming growth factor beta type I receptors at the local site during the acute phase of Shigella infection. 762 34

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.
 ...
PMID:Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells. 791 75

Treatment with a single low dose (80 to 800 ng) of interleukin-1 (IL-1) 24 h before a lethal bacterial challenge in granulocytopenic and in normal mice enhances nonspecific resistance. The mechanism behind this protection has only partially been elucidated. Since IL-1 induces production of tumor necrosis factor alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-activating factor (PAF), and arachidonic acid metabolites, we investigated the potential role of these substances in IL-1-induced protection. Low doses of murine TNF-alpha but not of human TNF-alpha enhanced survival, suggesting an effect via the type II TNF receptor rather than the type I TNF receptor, which has little species specificity. In line with this TNF-alpha-induced protection from infection, pretreatment with a low dose of a rat anti-murine TNF-alpha monoclonal antibody tended to inhibit IL-1-induced protection, suggesting a role of TNF-alpha as a mediator of IL-1-induced enhanced resistance to infection. Pretreatment with higher doses of anti-TNF-alpha, however, showed a dose-related protective effect per se, which could be further enhanced by a suboptimal dose of IL-1. A combination of optimal doses of anti-TNF-alpha and IL-1 produced an increase in survival similar to that produced by separate pretreatments. This lack of further enhancement of survival by combined optimal pretreatments suggests a similar mechanism of protection, most likely attenuation of deleterious effects of overproduced proinflammatory cytokines like TNF-alpha during lethal infection. Pretreatment with different doses of GM-CSF before a lethal Pseudomonas aeruginosa challenge in neutropenic mice did not enhance survival. Different doses of WEB 2170, a selective PAF receptor antagonist, of MK-886, a selective inhibitor of leukotriene biosynthesis, or of several cyclooxygenase inhibitors did not reduce the protective effect of IL-1 pretreatment. We conclude that IL-1-induced nonspecific resistance is partially mediated by induction of TNF-alpha and not by GM-CSF, PAF, and arachidonic acid metabolites. The mechanism of action of IL-1 seems to be similar to that of anti-TNF-alpha.
 ...
PMID:Roles of tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, platelet-activating factor, and arachidonic acid metabolites in interleukin-1-induced resistance to infection in neutropenic mice. 816 71

The aim of this study was to investigate whether interleukin (IL)-6 induces the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial plasma samples were obtained from cancer patients participating in phase I and II trials of recombinant IL-6 administered as a 120-hour continuous intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor p55 (TNFsRp55) levels were measured by specific radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment. Thereafter, levels promptly declined, reaching near baseline within 24 hours despite continuation of IL-6. TNFsRp55 plasma levels increased within 4 to 8 hours after initiating treatment and increased progressively throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels were below the detection limit in all samples tested. Peripheral blood mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56 +/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6 receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6-stimulated PBMC were below the detection limit of the assay. Macrophages generated by culturing monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than freshly isolated unfractionated or adherent PBMC and synthesized almost as much IL-1Ra when stimulated with IL-6 as with endotoxin. These results suggest that the antinflammatory properties of IL-6 may be due; in part, to the induction of IL-1Ra synthesis and the release of soluble TNF receptors. Our findings also suggest that tissue macrophages may be an important source of IL-6-induced IL-1Ra.
 ...
PMID:Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. 827 30

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-h TBP-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol myristate acetate (PMA) and cytokine-induced human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cell lines. Treatment of HIV-1-infected promonocytic U1 cells with r-h-TBP-1 or rhu TNFR:Fc reduced PMA-induced HIV-1 p24 antigen production in a concentration-dependent manner, with a maximal inhibition of approximately 90%. Maximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cells was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNFR:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant, granulocyte-macrophage colony-stimulating factor, interleukin-6, and TNF. Addition of r-hTBP-1 to U1 cells during the last 4 h of a 24 h incubation with PMA still inhibited p24 antigen production by 15%. U1 cells stimulated with 10(-7) M PMA released approximately 1 ng/ml endogenous TBP-1 with an initial peak observed at 1 h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition of U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR:Fc blocked PMA induction of nuclear factor (NK)- kappa B DNA-binding activity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HIV-1 expression and NK- kappa B DNA-binding activity in chronically infected U1 cells.
 ...
PMID:Soluble tumor necrosis factor receptors inhibit phorbol myristate acetate and cytokine-induced HIV-1 expression chronically infected U1 cells. 860 87

Epithelial cells potentially contribute to airways inflammation by antigen presentation and the production of proinflammatory cytokines. This study investigated the immunocytochemical localization of interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor (IL-1R Type I), tumor necrosis factor-alpha receptor (TNF-alpha R; 55kD), and human leukocyte antigen-DR (HLA-DR) on epithelial cells obtained by nasal brushing from 10 patients with allergic rhinitis in season and 15 healthy, nonallergic subjects. Six of the 15 nonallergic asymptomatic subjects had macroscopic evidence of nasal mucosal inflammation, and their brushings contained more than 10% neutrophils ("subclinical inflammation"). In normal control subjects, 8 +/- 7.5% of epithelial cells stained for HLA-DR, approximately one quarter stained for IL-8 and GM-CSF, and about one third stained positive for IL-1R and TNF-alpha R. The findings in subjects with allergic rhinitis in season and with subclinical neutrophilia were similar, and the numbers of cells staining for HLA-DR expression correlated with both neutrophil and lymphocyte content. These findings further support the conclusion that epithelial cells can contribute to inflammatory processes in the nasal mucosa. The findings emphasize the need to identify asymptomatic nasal mucosal inflammation in studies of the nasal mucosa.
 ...
PMID:GM-CSF, IL-8, IL-1R, TNF-alpha R, and HLA-DR in nasal epithelial cells in allergic rhinitis. 863 Jun 19


1 2 3 Next >>