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 effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was assessed in 17 patients with small cell lung cancer. GM-CSF was initially given alone by subcutaneous injection for 10 days at 50-500 micrograms/m2 per day. There was a significant rise in neutrophils and eosinophils and to a lesser extent in monocytes at all dose levels. During the next phase, patients received chemotherapy (etoposide, ifosfamide and doxorubicin), and GM-CSF was given on alternate cycles, the patients acting as their own controls, so that the amelioration of chemotherapy could be assessed. Despite partial abrogation of the neutropenia associated with chemotherapy (P = 0.04), GM-CSF failed to reduce the frequency of febrile episodes in association with neutropenia, with six episodes occurring on GM-CSF and seven while patients were not receiving GM-CSF after a total of 66 cycles of chemotherapy. After GM-CSF, there was a reduction in polymorph phagocytic ability and chemotaxis in 6/12 and 9/11 patients, respectively. Timed blood counts after GM-CSF administration showed that peak leucocytosis occurred at 8-12 h and fell to two-thirds of this level at 24 h. Toxicity consisting of lethargy, myalgia and bone pain occurred at all dose levels but was manageable. 2 patients had thromboembolism. This study failed to demonstrate a reduction in the infection risk associated with moderately intensive chemotherapy for small cell lung cancer despite the partial abrogation of neutropenia.
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PMID:Infection risk in patients with small cell lung cancer receiving intensive chemotherapy and recombinant human granulocyte-macrophage colony-stimulating factor. 131 26

Protein tyrosine kinases represent a subset of proteins that mediate signal transduction between the extracellular environment and the nucleus. We have previously described a coordinated upregulation between RNA transcripts of a tyrosine kinase, c-abl, and those of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6) in human marrow stromal cells (SVMSC). Moreover, an inverse relationship exists between expression of c-abl transcripts and those of extracellular matrix proteins such as type collagen I transcripts. In the present study, these inverse relationships were again seen in SVMSC when tyrosine kinase effects were enhanced by treatment of the cells with the tyrosine phosphatase inhibitor sodium orthovanadate. This suggests that tyrosine kinases are involved in the coordinate regulation of these genes.
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PMID:Sodium vanadate, a tyrosine phosphatase inhibitor, affects expression of hematopoietic growth factors and extracellular matrix RNAs in SV40-transformed human marrow stromal cells. 131 36

Several hormones and cytokines stimulate the cellular Na+/H+ antiporter and this stimulation may be a signal transduction mechanism to mediate gene expression. We find that tumor necrosis factor rapidly stimulates both the Na+/H+ antiporter and the accumulation of mRNA coding for granulocyte-macrophage colony-stimulating factor and interleukin-6 in fibroblasts. Further experiments show that these phenomena occur independent of each other.
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PMID:Tumor necrosis factor stimulates Na+/H+ antiporter in human fibroblasts: dissociation between intracellular alkalinization and cytokine mRNA accumulation. 131 73

We have attempted to determine whether interleukin-5 (IL-5), a cytokine that selectively affects eosinophil (as opposed to neutrophil) differentiation and activation, also modulates eosinophil migrational responses. Using a modified Boyden chemotaxis assay, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gave a weak locomotory response for eosinophils from normal nonatopic subjects (optimal at 10(-11), 10(-8), and 10(-9) mol/L, respectively), but not for eosinophils from subjects with an eosinophilia associated with asthma and/or allergic rhinitis. In contrast, IL-5 and IL-3 had no effect on neutrophils, while GM-CSF was chemotactic for neutrophils over a limited concentration range, optimal at 10(-8) mol/L. When eosinophils from normal subjects were incubated with IL-5 (10(-9) mol/L), the locomotory response to platelet-activating factor (PAF; 10(-8) mol/L, P less than .05), leukotriene B4 (LTB4; 10(-6) mol/L, P less than .01), and N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-8) mol/L, P less than .01) was significantly enhanced. The percentage enhancement of eosinophil locomotion by IL-5 was greater for eosinophils from normal as compared with subjects with an eosinophilia associated with asthma (P less than .05 for PAF and LTB4; P less than .01 for FMLP). Preincubation of eosinophils from normal subjects with IL-5 (10(-9) mol/L) attenuated the subsequent locomotory response to IL-5 (10(-12) and 10(-11) mol/L, P less than .05). Therefore, the observed refractoriness of eosinophils from eosinophilic subjects to both directional migratory and priming effects of IL-5 in vitro, may reflect a deactivation process resulting from prior exposure in vivo. The selective priming of eosinophil but not neutrophil locomotion by IL-5 suggests that this cytokine may play a significant role in the preferential accumulation of eosinophils at sites of allergic inflammation.
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PMID:Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. 131 89

Modulation of peripheral blood and mammary gland neutrophil function following in vitro exposure to recombinant bovine granulocyte-macrophage colony-stimulating factor (rBoGM-CSF) was studied. Bovine blood and mammary gland neutrophils were cultured for 9 h in media containing 0.005, 0.05 or 0.5 microgram/mL rBoGM-CSF. Neutrophils treated with rBoGM-CSF exhibited significantly more chemotactic and bactericidal activities and tended to produce more superoxide anion than control cells. The effects of rBoGM-CSF on bovine neutrophil populations appeared to be dose-dependent. The production of superoxide anion and the bactericidal activity of mammary gland neutrophils were consistently higher than blood neutrophils. Only moderate increases in lipopolysaccharide-induced mammary gland neutrophil functions were observed following incubation with rBoGM-CSF which suggests that there may be a threshold of immunomodulation for these prestimulated cells. It may be possible to augment the functional capacity of bovine neutrophil populations in vivo through the therapeutic application of rBoGM-CSF and consequently enhance resistance of dairy cattle to bacterial infections.
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PMID:Effects of recombinant granulocyte-macrophage colony-stimulating factor on bovine peripheral blood and mammary gland neutrophil function in vitro. 131 97

The clonal growth of cell lines from some human solid tumours can be stimulated by haematopoietic growth factors such as recombinant human (rh) interleukin-3 (IL-3) and rh granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Among these cell lines are the human colorectal adenocarcinoma cell line HTB 38 and the human small-cell lung cancer cell line HTB 119. Here we report on a series of experiments studying the influence of subcutaneously administered rhIL-3 and rhGM-CSF on the in vivo growth of HTB 38 and HTB 119 cell lines as xenografts in athymic nu/nu BALB/c mice. Beginning 1 day after transplantation of the tumour the cytokines were administered daily for 20 days as a subcutaneous bolus distant from the tumour lesion at dose levels up to 1 mg/m2/day. The cytokines caused no significant and reproducible growth modulation of the tumours in vivo.
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PMID:Effect of interleukin-3 and granulocyte-macrophage colony-stimulating factor on growth of xenotransplanted human tumour cell lines in nude mice. 131 97

Cultured human bronchial epithelial cells constitutively produce granulocyte-macrophage colony-stimulating factor (GM-CSF). The synthesis and release of GM-CSF is upregulated in bronchial epithelium of patients with symptomatic asthma and this may contribute to the local activation of inflammatory cells in their bronchial mucosa. The cause of this upregulation of GM-CSF expression is unknown, but an increased release of interleukin-1 (IL1) from other airway resident cells might be involved, as an increase in GM-CSF production can be induced in vitro in normal bronchial epithelial cells by IL1 and the airway secretions of asthmatics contain high amounts of this cytokine. In the present study, we have evaluated the effect of the anti-inflammatory and antiasthmatic drug, nedocromil sodium, on the spontaneous and IL1-induced expression of GM-CSF in cultured bronchial epithelial cells. This compound, at the concentration of 10(-5) M, reduced the IL1-induced increase in GM-CSF release from epithelial cells by more than 40%, but it did not affect the constitutive production of GM-CSF.
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PMID:Protective effect of nedocromil sodium on the IL1-induced release of GM-CSF from cultured human bronchial epithelial cells. 131 31

Receptors of the hematopoietin superfamily, including the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, lack a tyrosine kinase domain as well as other sequences indicative of a known signaling mechanism. In this report, we identify the serine/threonine kinase, microtubule-associated protein 2 (MAP2) kinase, as an intermediate in the GM-CSF signal transduction pathway. Treatment of peripheral blood neutrophils or terminally differentiated HL-60 cells with GM-CSF induced a rapid and dose-dependent increase in MAP2 kinase activity. Maximal activity occurred within 5 minutes and the kinetics of the response varied depending on the target cell (prolonged in neutrophils and transient in neutrophilic HL-60 cells). MAP2 kinase activity in these cells correlates with the induction of a 42-Kd tyrosine phosphoprotein. Furthermore, tyrosine phosphorylation is necessary for MAP2 kinase activation since its activity is inhibited by treatment with the tyrosine kinase inhibitor, erbstatin analog. These data suggest that tyrosine phosphorylation is important in GM-CSF-mediated signal transduction and that MAP2 kinase activation may be a central biochemical event involved in its signaling.
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PMID:Granulocyte-macrophage colony-stimulating factor activates microtubule-associated protein 2 kinase in neutrophils via a tyrosine kinase-dependent pathway. 131 28

Human polymorphonuclear leukocytes (PMN) preincubated overnight with 100 U/mL gamma-interferon (IFN-gamma) had an increased metabolic response, as measured by iodination and/or superoxide production, to stimulation by tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), formylmethionyl-leucyl-phenylalanine (FMLP), opsonized zymosan, and lipopolysaccharide (LPS), as compared with cells comparably preincubated in the absence of IFN-gamma. The decline in the staphylocidal activity of the stored PMN was also prevented in part by IFN-gamma, as was the depressed adherence of PMN stimulated with phorbol myristate acetate (PMA), FMLP, TNF, GM-CSF, and LPS. This protective effect of IFN-gamma on PMN function was associated with the prolonged surface expression of the complement receptor three (CR3) alpha-chain (CD11b), CR3 beta-chain (CD18), FcRII (CD32), and FcRIII (CD16), and the appearance of surface FcRI (CD64). The polymerase chain reaction (PCR) was used to amplify neutrophil RNA-derived cDNA recognized by synthetic oliogonucleotides designed from published nucleotide sequences for specific proteins. Using this procedure, mRNA for gp91-phox, p67-phox, p47-phox, CD64, two forms of CD32, CD16, CD11b, CD18, and actin were found to be depressed after overnight storage of neutrophils, and this decrease in steady-state mRNA levels was in part or totally prevented by IFN-gamma. CD64 and gp91-phox mRNA were generally increased by IFN-gamma to a level greater than that of freshly isolated neutrophils. Northern analysis of CD64 and p47 phox mRNAs confirmed the findings with the PCR method. These findings suggest that storage of PMN in a functionally active state is favored by the presence of IFN-gamma.
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PMID:Effects of gamma-interferon on human neutrophils: protection from deterioration on storage. 131 36

We previously proposed the hypothesis that the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) based on our observations that it is the dominant inducer of interleukin-1 (IL-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in RA synovial joint mononuclear (MNC) cells in culture. Since TNF-alpha acts via two membrane receptors, we have extended those studies to investigate the distribution of the p55 and p75 TNF receptors (TNF-R) in RA tissue. Surface receptor expression was quantitated by flow cytometry using monoclonal antibodies specific to the p55 (HTR-9) and the p75 (UTR-1) TNF-R. Both receptors were significantly increased on MNC isolated from the synovial membrane of RA patients compared to normal or RA peripheral blood MNC. Interestingly, the p75 TNF-R was increased both on large monocytic/macrophage-type cells and CD3+ lymphocytes. Furthermore, there was a significant increase in the proportion of CD3+ cells in RA synovial fluid expressing the p75 TNF-R, compared to matched peripheral blood MNC. In contrast to RA synovial MNC, p75 or p55 TNF-R expression was not significantly increased in osteoarthritis synovial MNC. In addition, Northern blot analysis indicated abundant expression of both p55 and p75 mRNA in RA synovial joint MNC. This was in contrast to normal peripheral blood MNC cells which contained little or no constitutive TNF-R mRNA; following stimulation with phytohemagglutinin and IL-2, a rapid and transient expression of both receptor mRNA was induced. These results, therefore, indicate that in RA synovial joint tissue there is up-regulation of both p55 and p75 TNF-R mRNA and surface protein expression, and with the presence of TNF-alpha in RA tissues, these results provide support to our hypothesis that TNF-alpha is of critical importance in the pathogenesis of RA.
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PMID:Enhanced expression of tumor necrosis factor receptor mRNA and protein in mononuclear cells isolated from rheumatoid arthritis synovial joints. 132 May 71


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