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)

Endothelial cells (EC) may regulate both local and systemic aspects of inflammation through the synthesis of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-6 (IL-6). EC are known to synthesize these cytokines in response to interleukin-1 (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). In this paper, we illustrate the effect of interleukin-4 (IL-4) in reducing the synthesis of GM-CSF by EC stimulated with IL-1 alpha, TNF-alpha, or LPS. This is compared with the previously reported strong synergy between IL-4 and IL-1 alpha, TNF-alpha, or LPS in the synthesis of IL-6 by EC. No clear effect of IL-4 was seen in the synthesis of G-CSF or M-CSF. The range of concentrations of IL-4 at which these effects were seen was identical for both reduced GM-CSF synthesis and increased IL-6 synthesis. The effect of IL-4 on IL-6 synthesis was seen by 4 h of treatment, while that on GM-CSF was apparent between 4 and 8 h. It is suggested that these contrasting effects of IL-4 may reflect a biological role for this cytokine in the regulation of leukocytosis and the acute phase response.
Lymphokine Cytokine Res 1993 Apr
PMID:Contrasting effects of interleukin-4 on colony-stimulating factor and interleukin-6 synthesis by vascular endothelial cells. 832 81

Cytokine-activation pathways in mast cells are supposed to play a significant role in host defense mechanisms and allergic reactions. Interleukin-4 (IL-4) is a well-characterized regulator of growth and function of mast cells. The human mast cell line HMC-1 was established from a patient suffering from mast cell leukemia and was shown to expose IL-4 binding sites. In the present study, the effects of recombinant human (rh) IL-4 and other rh cytokines (IL-2, IL-3, IL-6, IL-8) on expression of cytokine mRNA in HMC-1 cells were examined by Northern blot analysis using oligonucleotide probes. Tumor necrosis factor alpha (TNF-alpha) and IL-1 beta transcripts were found to be expressed constitutively in HMC-1 cells, whereas transcripts for IL-3, IL-4, IL-5, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) could not be detected. Of all cytokines tested, rhIL-4 was found to down-regulate IL-1 beta mRNA expression and formation of immunoreactive IL-1 beta protein in HMC-1 cells. The effect of IL-4 on IL-1 beta gene product expression was time- and dose-dependent (maximum effects obtained with 100 U/mL of rhIL-4). No effect of IL-4 on expression of TNF-alpha mRNA in HMC-1 cells was observed. These results raise the possibility that human mast cells are a source of both TNF-alpha and IL-1 beta. Furthermore, our study provides evidence that IL-4 regulates IL-1 beta gene product expression in HMC-1 cells. The HMC-1 cell line should be a useful tool for studying cytokine activation pathways in human mast cells.
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PMID:Tumor necrosis factor alpha and interleukin-1 beta mRNA expression in HMC-1 cells: differential regulation of gene product expression by recombinant interleukin-4. 833 Jun 51

Cloned T lymphocytes (TLC) of the CD4+CD8- phenotype established from peripheral blood of a patient with idiopathic hypereosinophilic syndrome (HES) were found to release a lineage-specific eosinophilic colony-stimulating factor (Eo-CSF). The present study was undertaken to identify the lymphokine accounting for this Eo-CSF activity. Comparison of TLC-derived Eo-CSF with recombinant human interleukin-5 (rhIL-5), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and recombinant human interleukin-3 (rhIL-3) by in vitro clonogenic assays revealed similar bioactivity of HES-derived Eo-CSF and IL-5. Neutralization studies using specific antibodies against IL-5, GM-CSF and IL-3 confirmed that IL-5 mainly accounts for the Eo-CSF activity in all 9 HES-derived TLC tested. Eosinophilic colony (CFU-Eo) formation supported by conditioned media of the TLC was significantly inhibited in all clones by addition of anti-IL-5 monoclonal antibody (MAB) to the conditioned media. Inhibition by anti-IL-5 MAB was specific and dose-dependent. In 2 of the 9 clones, anti-GM-CSF antibodies could partially neutralize the Eo-CSF activity in the conditioned media. In 4 clones, addition of a combination of anti-IL-5 MAB and anti-GM-CSF antiserum to the conditioned media reduced CFU-Eo formation significantly more than addition of anti-IL-5 MAB alone. In none of the TLC could a significant role for IL-3 in eosinophilic colony formation be shown. These results were confirmed at the mRNA level. Cytokine transcripts were detected by reverse transcription (RT) and subsequent polymerase chain reaction (PCR). Under the same experimental conditions, all HES-derived TLC, but only one third of tested TLC from healthy donors, expressed IL-5 mRNA 5 days after stimulation. In control TLC with inducible IL-5 mRNA expression, IL-5 transcripts were found for only 3 days after stimulation. In contrast, HES-derived TLC contained IL-5 mRNA at least until day 18 after restimulation. All HES clones expressed GM-CSF mRNA upon stimulation. Two HES-derived TLC were found to lack IL-3 mRNA even after stimulation. Whereas IL-5 was expressed abundantly in all HES-clones, the intensity of PCR products for GM-CSF and IL-3 showed striking differences. Our in vitro results suggest that IL-5 produced by activated CD4+ T lymphocytes plays a crucial role in the induction of eosinophilia in HES. In addition, GM-CSF but not IL-3 seems to contribute partially to the increased eosinophil production in HES.
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PMID:Interleukin-5 is the predominant eosinophilopoietin produced by cloned T lymphocytes in hypereosinophilic syndrome. 842 73

Cytokine LD78 is a human counterpart of the mouse macrophage inflammatory protein 1 alpha/hematopoietic stem cell inhibitor. Promoters of the LD78 alpha and LD78 beta genes showed similar inducible activities in two leukemic cell lines, K562 and Jurkat, but the induction mechanisms differed between the two cell lines. Further characterization of the LD78 alpha promoter indicated that multiple positive and negative regulatory elements are present, some of which are differentially required for induction and repression of the promoter activity in different cells. One of the negative regulatory elements, ICK-1, functioned in both cell lines in the absence and presence of stimulation and was shown to be a recognition site for positive and negative transcriptional factors. This ICK-1 element contained a direct repeat, and similar repeats were also found in the negative regulatory elements of hematopoietic growth factor interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoters. Nuclear extracts from K562 and Jurkat cells formed several protein-DNA complexes with the LD78 alpha ICK-1 element, one of which was also observed with the IL-3 and GM-CSF ICK-1 elements. Results from in vivo and in vitro analyses suggested that the protein forming this complex functions as a negative factor. The binding affinity of this protein, ICK-1A, to the LD78 alpha ICK-1 element was low and was significantly affected by the incubation temperature and the salt concentration in the binding buffer. ICK-1B, another protein bound specifically by the LD78 alpha ICK-1 element, was shown to be a positive factor important for induction of the promoter. These results suggested that ICK-1A plays an important role in balanced expression of LD78, IL-3, and GM-CSF during hematopoietic cell growth and differentiation.
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PMID:Characterization of cytokine LD78 gene promoters: positive and negative transcriptional factors bind to a negative regulatory element common to LD78, interleukin-3, and granulocyte-macrophage colony-stimulating factor gene promoters. 847 41

Interferon-gamma (IFN-gamma) is a priming agent of polymorphonuclear neutrophilic granulocyte (PMN) oxygen metabolism, and protein kinase C (PKC) is traditionally believed to play a central role in activation of this oxygen metabolism. In the present study, we have shown that the PKC activity in PMN is affected by IFN-gamma. After only 2 minutes exposure to IFN-gamma (100 U/ml), PKC activity was significantly increased in the noncytosolic fraction of the cells. This increase was transient, but toward the end of the priming period of 2 h, the membrane-associated PKC activity increased again to about 152% of control. In the cytosolic fraction, a small and hardly detectable decrease in PKC activity was observed. Treatment of PMN with granulocyte-macrophage colony-stimulating factor (GM-CSF), another PMN priming agent, showed no significant effects on the PKC activity. When the cells were stimulated with the bacterial peptide fMLP after a priming period with IFN-gamma or GM-CSF for 2 h, no significant difference between treated and control cells could be observed. PMN oxygen metabolism, measured by flow cytometry as an accumulation of the fluorescent compound dichlorofluorescein, was in these experiments significantly primed by IFN-gamma, both at baseline and when stimulated with fMLP. The protein kinase C inhibitors H7 and Ro31-8220 blocked the fMLP responses to some extent, but not completely. However, no significant difference between fMLP responses in control and IFN-gamma-treated cells could be detected after administration of inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
J Interferon Cytokine Res 1995 Sep
PMID:Interferon-gamma affects protein kinase C activity in human neutrophils. 853 5

While success of autologous bone marrow transplantation (BMT) for malignancies largely depends on the cytotoxicity of the ablative regimen, achievement of relapse-free survival after allogeneic BMT is thought to be enhanced by immunologic effects. We therefore investigated in vivo and in vitro production of interferon-gamma (IFN-gamma), soluble interleukin-2 (IL-2) receptor alpha-chain (sCD25), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients before and during various time periods up to 2 years after autologous and allogeneic BMT. Cytokine levels were assessed in patient plasma and in supernatants of patient-derived peripheral blood mononuclear cells (PBMNC) cultured for 3 days in the presence of T cell-specific stimulation via CD3 plus IL-2. Our studies show that IFN-gamma plasma levels are decreased in autologous graft recipients before and during the first 30 days posttransplant. In allogeneic graft recipients, IFN-gamma plasma levels are also decreased during the first 30 days posttransplant, but otherwise are comparable to normal control (NC) values. In vitro stimulated PBMNC from autologous graft recipients also exhibit an IFN-gamma production defect before and during the first 30 days posttransplant. In contrast, before and up to 30 days after allogeneic BMT, stimulated IFN-gamma production is comparable to NC values but then gradually decreases, reaching its trough levels at between 61 and 180 days post-BMT. The IFN-gamma production defects in both patient groups seem to be specific, as sCD25, TNF-alpha, and GM-CSF production in stimulated PBMNC is normal or even enhanced at any time after autologous or allogeneic BMT. Deficient IFN-gamma production in patient-derived PBMNC does not correlate with variation in monocyte, T cell, or natural killer (NK) cell numbers during the posttransplantation course.
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PMID:Time course of interferon-gamma production deficiency after autologous and allogeneic stem cell transplantation for malignancies. 854 45

We investigated the effects of stem cell factor (SCF) on the growth of blast clonogenic cells from 27 patients with acute myeloblastic leukemia (AML) and 3 patients with chronic myelocytic leukemia in myeloid crisis. SCF alone showed a significant stimulatory activity in 15 of 30 patients (50%). A marked reduction in the number of blast cell colonies supported by SCF alone was noted by the addition of neutralizing antibody (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF). Ab against interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) also moderately reduced the number of colonies, whereas Ab against granulocyte CSF (G-CSF) failed to do so. All four Ab together completely abolished the growth in 5 of 6 patients tested. c-kit antisense oligonucleotides reduced the colony formation supported by IL-3 or G-CSF or, in the absence of growth factor, in only 2 of 10 patients tested. SCF caused stimulation by acting synergistically with G-CSF, GM-CSF, IL-3, IL-6, IL-9, IL-11, and IL-12 in 20 of 27 (74%), 17 of 27 (63%), 14 of 28 (50%), 9 of 28 (32%), 1 of 15 (7%), 3 of 28 (11%), and 2 of 15 (13%) patients, respectively. Thus, SCF alone or in combination with some other factor stimulated the growth in 27 of 30 (90%) patients. Of 3 nonresponders, 2 were AML, M3 at presentation. G-CSF at the optimal concentration increased the sensitivity of blasts to SCF. Taken together, SCF acting in combination with other factors, but not alone, stimulates the growth of blast clonogenic cells. GM-CSF, IL-6, and TNF-alpha may be produced endogenously, whereas G-CSF and SCF may be supplied exogenously. Autocrine regulation of the growth of blasts seems to increase the responsiveness of the cells to any of these factors, allowing them to achieve a highly active growth state.
J Interferon Cytokine Res 1995 Oct
PMID:Roles of stem cell factor in the in vitro growth of blast clonogenic cells from patients with acute myeloblastic leukemia. 856 3

When granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated human neutrophils were challenged with the chemotactic factor fMet-Leu-Phe, it was possible to detect a time-dependent increase in the hydrolytic (as measured by the production of phosphatidic acid, PA) and the transphosphatidylation (as measured by the production of phosphatidylethanol, PEt) activities of phospholipase D in intact cells prelabeled with a radioactive fatty acid. Both activities were inhibited by preincubation of cells with genistein. Appropriate conditions were developed to test the PLD transphosphatidylation activity against exogenous phosphatidylcholine (PCho) in an in vitro system. As in intact cells, increased PLD activity could be detected in cell lysates obtained from fMet-Leu-Phe-treated cells compared with controls. When lysates were immunoprecipitated with antiphosphotyrosine antibodies, a PLD activity was found only in immune complexes that were prepared from fMet-Leu-Phe-treated cells. Conversely, no activity was found in lysates immunoprecipitated with an irrelevant antibody (GTPase-activating protein, GAP) that nevertheless was able to recognize a tyrosylphosphorylated form of GAP, as demonstrated by western blotting. These data suggest that a PCho-PLD, or a tightly bound protein, is tyrosine phosphorylated during cell activation.
J Interferon Cytokine Res 1995 Oct
PMID:Immunoprecipitation of a phospholipase D activity with antiphosphotyrosine antibodies. 856 10

We have examined basal and lipopolysaccharide (LPS)-induced release of epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-regulated peptide alpha (GRO alpha), leukaemia inhibitory factor (LIF), macrophage inflammatory protein-1a (MIP-1 alpha) and platelet-derived growth factor-AB (PDGF-AB) in peripheral blood mononuclear cells (PBMC) from 20 persons with either high (n = 10) or low (n = 10) levels of high-density lipoprotein (HDL). PBMC were incubated with 100 ng LPS/ml for up to 160 h, and showed a significantly higher release of the chemokines GRO alpha (P = 0.04) and MIP-1 alpha (P < 0.01) in persons with high HDL, whereas levels of GM-CSF were similar. Levels of EGF, LIF and PDGF-AB were always low, and remained unaltered during 160 h of incubation. These findings indicate that PBMC from persons with high or low levels of HDL have different functional properties, of importance in cell recruitment and activation.
Cytokine 1995 Aug
PMID:LPS-induced release of EGF, GM-CSF, GRO alpha, LIF, MIP-1 alpha and PDGF-AB in PBMC from persons with high or low levels of HDL lipoprotein. 858 Mar 73

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
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PMID:Immune-mediated side-effects of cytokines in humans. 863 83


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