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)

The high affinity receptor of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is a heterodimer composed of two members of the cytokine receptor superfamily. GM-CSF binds to the alpha-subunit (GM-R alpha) with low affinity and to the receptor alpha beta complex (GM-R alpha beta) with high affinity. The GM-CSF.GM-R alpha beta complex is responsible for biological activity. Interactions of the N-terminal helix of mouse GM-CSF with mGM-R alpha beta were examined by introducing single alanine substitutions of hydrophilic residues in this region of mGM-CSF. The consequences of these substitutions were evaluated by receptor binding and biological assays. Although all mutant proteins exhibited near wild-type biological activity, most were defective in high affinity receptor binding. In particular, substitution of Glu-21 with alanine abrogated high affinity binding leaving low affinity binding unaffected. Despite near wild-type biological activity, no detectable binding interaction of this mutant with mGM-R beta in the context of mGM-R alpha beta was observed. Cross-linking studies showed an apparent interaction of this mutant protein with mGM-R alpha beta. The deficient receptor binding characteristics and near wild-type biological activity of this mutant protein demonstrate that mGM-CSF receptor activation can occur independently of high affinity binding, suggesting that conformational changes in the receptor induced by mGM-CSF binding generate an active ligand-receptor complex.
J Biol Chem 1992 Dec 15
PMID:High affinity ligand binding is not essential for granulocyte-macrophage colony-stimulating factor receptor activation. 146 41

Cytokines are known to play an important role in host defense by regulating the function, growth, and differentiation of the cells of the immune system. We hypothesize that, in the tumor microenvironment, tumor cells and resident tissue cells (e.g., fibroblasts) also produce cytokines that may regulate the local immune response to tumors. Initially, homogenates of eight head and neck squamous cell carcinomas (HNSCC) were assayed for the presence of interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) to establish the presence of these cytokines in the tumors in vivo. We detected IL-1 in all tumor homogenates and IL-4, IL-6, and GM-CSF in some homogenates. To assess the ability of HNSCC to produce these cytokines, supernatants of short-term primary cultures of HNSCC were assayed for the same cytokines. No IL-1 was detected, although baseline levels of IL-4, IL-6, and GM-CSF were present. However, the stimulation of primary tumor cultures with exogenous IL-1 induced or significantly enhanced production of IL-4 (p < 0.01), IL-6 (p < 0.001), and GM-CSF (p < 0.02). These results support our hypothesis that HNSCC secrete cytokines that may influence the response of local immune cells. Our data also suggest that IL-1 may have a central role in regulating the local immune response through the enhancement or induction of cytokine production by tumor and/or resident tissue cells.
Am J Surg 1992 Dec
PMID:Cytokine expression by head and neck squamous cell carcinomas. 146 1

It is now generally accepted that many cytokines are involved in the pathogenesis of autoimmune disease, either directly by causing tissue destruction or indirectly through the activation of autoreactive and inflammatory cells. Thus, cytokines, such as tumor necrosis factor-alpha, are implicated in the pathogenesis of rheumatoid arthritis based on in vitro studies on synovial tissue from patients with rheumatoid arthritis, which suggest that the effects of tumor necrosis factor-alpha are amplified by its potential to induce other pro-inflammatory cytokines, such as interleukin-1 and granulocyte-macrophage colony-stimulating factor. Transgenic mouse technology has shown that mice expressing the human tumor necrosis factor-alpha gene develop a polyarthritis. Interleukin-2 has also been identified by transgenic technology as a cytokine involved in the pathogenesis of insulin-dependent diabetes mellitus through the activation and stimulation of growth of autoreactive T cells.
Curr Opin Immunol 1992 Dec
PMID:Cytokines in autoimmunity. 146 99

The UT-7 cell line was established from a patient with a megakaryoblastic leukemia (Komatsu et al, Cancer Res 51: 341, 1991). Its proliferation is strictly dependent on the presence of hematopoietic growth factors including erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3). We investigated the differentiation capacities of this cell line under the action of several growth factors, using immunomarkers, flow cytometry, and ultrastructural techniques. In the presence of GM-CSF and IL-3, eosinophil and basophil promyelocytes were detected, as well as a few cells with erythroid and megakaryocytic (MK) differentiation features. In contrast, Epo induced a marked erythroid differentiation with an increase of glycophorin A expression, accompanied by a few hemoglobinized cells. Differentiation induced by the growth factors took 24 to 48 hours to begin, and increased with cell passages to a plateau at 2 weeks of culture. However, this was not only due to a cell selection because the differential effects of Epo and GM-CSF were observed from a single cell clone and the phenotype could be reversed by opposite growth factors, even after a long period of culture. We subsequently investigated the phenotype of UT-7 in the presence of combinations of Epo, IL-3, and GM-CSF, and showed that GM-CSF and IL-3 act predominantly over Epo. This effect was mediated by a rapid downmodulation of Epo receptors by GM-CSF at messenger RNA and binding sites levels, without a change in receptor affinities. On the other hand, Epo had no effect on number and affinity of GM-CSF receptors. This study shows that UT-7 is a growth factor-dependent pluripotent cell line in which commitment may be directed by a hierarchical action of growth factors through an early and rapid transmodulation of growth factor receptors.
Blood 1992 Dec 15
PMID:Granulocyte-macrophage colony-stimulating factor and erythropoietin act competitively to induce two different programs of differentiation in the human pluripotent cell line UT-7. 146 15

We have evaluated the effect of intravenous infusions of granulocyte-macrophage colony-stimulating factor (GM-CSF) in ten patients undergoing autologous bone marrow transplantation after total body irradiation (11 Gy) and cyclophosphamide (120 mg/kg) conditioning for malignant lymphomas or acute lymphoblastic leukaemias. Mild side effects related to GM-CSF were seen in six patients, of whom one chose to discontinue treatment. Compared to a historic control group consisting of six patients treated with an identical conditioning regimen, a tendency was seen towards a more rapid neutrophil regeneration and a decreased need for erythrocyte transfusions. Moreover, a statistically significant improvement in thrombocyte related parameters was demonstrated. In contrast, there were no significant differences in severe toxicity, days on i.v. antibiotics, septic episodes or duration of hospitalization. In conclusion, it seems that GM-CSF treatment is of value in patients undergoing AKMT.
Ugeskr Laeger 1992 Dec 21
PMID:[Granulocyte-macrophage colony-stimulating factor. Treatment of patients with highly malignant lymphomas and acute lymphoblastic leukemias after autologous bone marrow transplantation]. 849 41

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are hematopoietic growth factors that have been shown to induce proliferation and activation of inflammatory cells, and may play a role in allergic reactions. Since little is known about the involvement of cytokines in allergic inflammation in the lung, the levels of GM-CSF and IL-3 were measured in bronchoalveolar lavage (BAL) fluids obtained in the late phase after segmental lung antigen (Ag) challenge in 14 allergic rhinitis subjects with or without bronchial asthma. BAL fluids either after Ag (ragweed, dust mite, or timothy) or saline control challenge were recovered 19 h later. In 6 of the 14 patients, BAL fluids were concentration-dialyzed (20x) and assayed for cytokine activity. Cytokine assays were performed using the human megakaryocytic leukemic cell line M-07e, which is responsive to either GM-CSF or IL-3. The level of GM-CSF-equivalents was approximately 25 times higher in Ag-challenged sites (49.9 +/- 12.7 pg/ml; mean +/- SEM), compared to saline challenge sites (2.2 +/- 1.0, p < 0.01, n = 9). Neutralization experiments using a polyclonal specific antibody (Ab) against GM-CSF and IL-3 revealed that the bulk of the activity was GM-CSF. BAL fluids from Ag- and saline-challenged sites in one nonatopic subject contained no significant GM-CSF activity. Furthermore, the level of GM-CSF in Ag-challenged BAL fluid and the percentage of eosinophils in BAL from each subject correlated significantly (r = 0.73, p < 0.005, n = 14).(ABSTRACT TRUNCATED AT 250 WORDS)
Lymphokine Cytokine Res 1992 Dec
PMID:Production of granulocyte/macrophage colony-stimulating factor in human airways during allergen-induced late-phase reactions in atopic subjects. 147 81

Eosinophil function is regulated by several cytokines, including interleukin-3 (IL-3), IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Culture of human eosinophils with IL-3 produced a marked, dose-dependent up-regulation of CR3 expression. This was maximal after 1 day in culture and dependent on protein and RNA synthesis, as demonstrated by inhibition with cycloheximide and actinomycin D, respectively. IL-5 and GM-CSF had a similar effect on eosinophil complement receptor type 3 (CR3) expression, but the maximal response to IL-5 was always less than to IL-3 or GM-CSF. Dexamethasone inhibited the Il-3-induced up-regulation of CR3 expression in a dose-dependent manner, with an IC50 of 5 x 10(-8) M. This study demonstrates the effect of IL-3, IL-5 and GM-CSF on eosinophil CR3 expression and confirms the capacity of eosinophils to modify their phenotype through de novo protein synthesis. This process could be inhibited by physiological concentrations of glucocorticoids, thus providing an additional mechanism for their mode of action in allergic disease.
Immunology 1992 Dec
PMID:Interleukin-3-induced up-regulation of CR3 expression on human eosinophils is inhibited by dexamethasone. 149 20

Platelet-activating factor (PAF; 1-alkyl-2-acetyl-sn-glycero-3- phosphocholine) is a mediator involved in the pathogenesis of inflammatory diseases associated with tissue eosinophil infiltration. Previous studies utilizing bioassay or assaying enzymes associated with PAF biosynthesis have suggested that human eosinophils produce PAF. The present study has extended these initial studies by identifying and quantifying the different PAF molecular species and analogues synthesized by human eosinophils in response to A23187 and f-Met-Leu-Phe (FMLP). Gas chromatography-mass spectrometric analysis indicated that A23187-stimulated eosinophils produce at least three molecular species of PAF. The predominant species is 1-hexadecyl-2-acetyl-GPC (16:0) followed by 1-octadecyl-2-acetyl-GPC (18:0) and 1-octadecyl-2-acetyl-GPC (18:1). Eosinophils stimulated with FMLP produce approximately 100-fold smaller quantities of PAF relative to those produced in response to A23187 and only the 16:0 molecular species could be measured. A small percentage (comprising between 2 and 5%) of the 2-acetylated phospholipids produced by eosinophils was the 1-acyl analogue of PAF. Long-term (72 hr) incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in a three- to fourfold increase in PAF synthesis from eosinophils stimulated with FMLP, without changes in the profile of PAF molecular species or in the percentage of the 1-acyl analogue of PAF. These data indicate that human eosinophils can produce various molecular species of PAF and that this process can be quantitatively enhanced by GM-CSF.
Immunology 1992 Dec
PMID:Characterization of platelet-activating factor synthesized by normal and granulocyte-macrophage colony-stimulating factor-primed human eosinophils. 149 22

We studied neutrophil functions (phagocytosis, intracellular killing and chemotaxis with or without recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and T cell functions (lymphocyte proliferation and production of GM-CSF in response to phytohemagglutin (PHA)) to clarify host defense mechanisms in the elderly. There was no significant difference in phagocytic activity of neutrophils between the elderly and control young adults. rhGM-CSF enhanced phagocytosis by neutrophils, and a similar degree of enhancement was obtained in both groups. Killing activity of neutrophils evaluated by the new Nitroblue tetrazolium reduction test in the elderly was significantly lower than that in young adults (p < 0.001), however, pretreatment of neutrophils with rhGM-CSF resulted in an increase of killing activity in the elderly, raising their response to a level comparable to that of young adults pretreated with rhGM-CSF. There was no significant difference between the elderly and young adults in chemotaxis of neutrophils. rhGM-CSF alone did not prime chemotaxis, but primed chemotaxis in response to chemoattractant (N-formyl-methionyl-leucyl-phenylalanin) in both individuals. Lymphocyte proliferation and production of GM-CSF in response to PHA in the elderly were significantly lower than those in the young adults (p < 0.001, p < 0.05, respectively). These results indicated that impaired T cell functions may contribute, at least in part, to susceptibility to bacterial infection in the elderly.
Nihon Ronen Igakkai Zasshi 1992 Dec
PMID:[Role of neutrophil and T cell functions in host defense mechanisms of the elderly]. 149 47

Proliferation of microglial cells commonly occurs in the response of the central nervous system to injury, but little is known about how this process is regulated in vivo. Here we have studied the expression of receptors to macrophage colony-stimulating factor (MCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF) in the normal and regenerating rat facial motor nucleus using receptor immunocytochemistry and in situ ligand binding methods. Under normal conditions, immunocytochemical staining with anti-MCSF receptor (MCSFR) antibody revealed a moderate but selective labelling of microglia-like cells of the facial motor nucleus. This immunostaining also colocalized with MUC102, a new monoclonal antibody raised against microglial cells in the rat central nervous system. Axotomy of the facial nerve led to a rapid increase in MCSFR-staining intensity 1 day after injury, which became maximal 7 days postoperatively and then decreased. A similar but somewhat slower increase was also observed for the specific [125I]MCSF binding with a maximum at 7 days. Specific [125I]GMCSF binding also increased, peaking at 4 days postoperatively and then rapidly decreasing to normal levels at 21 days after axotomy. In summary, axotomy of the facial nerve led to a rapid increase in receptors for MCSF and GMCSF, which coincided with the pattern of microglial proliferation in the regenerating facial motor nucleus. This apparent up-regulation of receptors for microglial growth factors may play an important role in preparing the microglia to participate in the cellular response to injury in the regenerating central nervous system.
J Neurosci Res 1991 Dec
PMID:Increase of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor receptors in the regenerating rat facial nucleus. 166 63


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