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)

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

Early studies of patients dying from status asthmaticus revealed marked inflammation of the bronchial tree. Subsequent histological studies of the airways and examination of bronchoalveolar lavage fluid of subjects with mild asthma have confirmed the presence of airway inflammation in life. There is epithelial edema and desquamation, subepithelial deposition of collagen and fibronectin, and an inflammatory cell infiltrate in the mucosa. There are increased numbers of activated eosinophils, CD25-positive T lymphocytes, and immature macrophages with the phenotypic characteristics of blood monocytes. An increased expression of HLA class II is present on epithelium, macrophages, and other infiltrating cells. The severity of clinical asthma correlates with several measurements of the severity of the inflammatory response, suggesting a crucial role for airway inflammation in the pathophysiology of the disease. There is considerable interest and research into the mechanisms underlying the pathogenesis and maintenance of the inflammatory response in asthma. The development and maintenance of the inflammatory response in asthma is likely to be a consequence of a complicated interaction between various cells and the mediators they generate. The characterization of an ever-increasing number of cytokines is of particular interest. Interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor are hematopoietic growth factors that increase the survival of eosinophils in culture and enhance certain eosinophil functions, such as mediator generation and toxicity. Alveolar macrophages derived from asthmatic subjects produce twofold to threefold more GM-CSF than do those from normal control subjects. Using in situ hybridization, the presence of IL-5 mRNA has been demonstrated in bronchial biopsies from asthmatic subjects. Thus IL-3, IL-5, and GM-CSF influence eosinophil function and survival, and may be generated by T lymphocytes and/or alveolar macrophages within the airways in asthma. In addition to these three cytokines, IL-4 and interferon-gamma may be crucial to the regulation of IgE biosynthesis. TNF-alpha and IL-1 are potentially important in the up-regulation of endothelial adhesion molecules. An important step in the recruitment of leukocytes to an inflammatory focus is margination to the vascular endothelium. Our understanding of the molecular events involved in migration of leukocytes to an inflammatory focus has been advanced by the discovery and characterization of a variety of cell adhesion molecules. The potential role of ELAM-1 and ICAM-1 in allergic inflammation is suggested by their up-regulation on vascular endothelium in association with late cutaneous responses to allergen and by their role in certain primate models of asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pathobiology of bronchial asthma. 150 77

Members of the beta 1 subfamily of integrins, a group of heterodimeric transmembrane adhesion receptors, mediate the attachment of monocytes and macrophages to cell matrix proteins such as fibronectin, collagen, and laminin. Such interactions are likely of considerable importance during inflammatory responses, when monocytes are recruited to, and retained in, extravascular sites. Because of the complexity of the interactions that befall monocytes during an inflammatory response, it seems likely that expression of adhesion receptors on monocytes would be precisely regulated. In the present study, we have examined the mRNA expression of alpha 5 and beta 1 subunits of the fibronectin receptor in purified human peripheral blood monocytes and monocyte-derived macrophages cultured in the absence or presence of various agents known to induce activation and/or differentiation. Incubation under nonadherent conditions for 6 h with interferon (IFN)-gamma or bacterial lipopolysaccharide (LPS) resulted in a decreased expression of both alpha 5 and beta 1 mRNAs in freshly isolated monocytes. In contrast, incubation with IFN-alpha did not result in a decreased expression of alpha 5 mRNA, although a moderate decrease in beta 1 mRNA was observed. Culture with granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, phorbol myristic acetate, or plasma fibronectin (under nonadherent and adherent conditions) did not result in a change in levels of alpha 5 or beta 1 transcripts. In contrast to the results obtained with freshly isolated monocytes, incubation for 6 h with IFN-gamma or LPS did not alter the expression of alpha 5 or beta 1 mRNA in macrophages derived by culture of monocytes for 6 days in Teflon beakers. Our results indicate that IFN-gamma and LPS, both of which may be present in inflammatory sites, downregulate the mRNA expression of fibronectin receptor subunits in monocytes. Moreover, alpha 5 and beta 1 gene regulation by these agents is apparently dependent on the differentiation stage of the cells. This may provide a mechanism by which extravasating monocytes detach from extracellular matrix proteins, present in subendothelial basement membranes and deposited in sites of inflammation, in order to pursue other activities.
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PMID:Regulation of fibronectin receptor (alpha 5 beta 1) mRNA expression in human monocytes and monocyte-derived macrophages by activation/differentiation signals. 183 43

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.
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PMID:Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line. 201 98

Eleven patients with myelodysplastic syndrome (MDS) and bone marrow fibrosis were identified out of a group of 15 patients with MDS who received recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) as part of a phase I/II trial. Bone marrow biopsies were obtained before and after one or more courses of GM-CSF at 250 micrograms/m2 administered as a 12-h infusion each day for 14 days. The biopsies were blindly evaluated and reticulin formation and collagen deposition were graded on a scale of 0-4. Fibrosis unequivocally increased in three patients and decreased in three patients. There were equivocal increases in an additional two patients and decreases in one subject. It was unchanged in one subject and unevaluable in one patient. Although patients in whom fibrosis increased tended to have smaller increases in neutrophil and reticulocyte counts on therapy, the difference was not statistically significant. In this small group of patients, it was not possible to determine clinical features that predicted response. Although GM-CSF can lead to partial resolution of marrow fibrosis in some individuals, it can also accelerate its deposition; improvement in granulocyte or reticulocyte count does not preclude increasing marrow fibrosis. Thus, the use of GM-CSF in patients with myelodysplasia with marrow fibrosis must be undertaken with caution.
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PMID:Variable effect of recombinant human granulocyte-macrophage colony-stimulating factor on bone marrow fibrosis in patients with myelodysplasia. 218 31

We investigated the ability of the purified recombinant human cytokines: tumor necrosis factor-alpha (rTNF), granulocyte-macrophage colony-stimulating factor (rGM-CSF), interleukin-1 beta (rIL-1), interleukin-3, and tumor necrosis factor-beta (rTNF-beta) to stimulate neutrophil adherence (NA) to basement membranes (BMs) of stratified squamous epithelia pretreated with autoantibodies (ABM) specific for the BM matrix protein, type-VII collagen. rTNF, rGM-CSF, rIL-1, and rTNF-beta, but not IL-3, stimulated NA and stimulation was ABM- and cytokine-concentration-dependent. Stimulation was cytokine-specific and not due to endotoxin since it was significantly inhibited by cytokine-specific antibodies but not by polymyxin B (PB). rTNF and rGM-CSF were the most potent stimulators, were effective at concentrations less than 0.067 ng/ml, and stimulated NA greater than 600%. Relative potency was: rTNF = rGM-CSF greater than rTNF-beta greater than rIL-1. Stimulation by rTNF was due to a rapid, time-dependent effect on the neutrophil, and NA appeared to be dependent, in part, on the low-affinity neutrophil receptor for IgG, Fc(gamma)RIII, because it could be specifically inhibited by monoclonal antibody (3G8) to Fc(gamma)RIII. These results suggest that rTNF, rGM-CSF, rIL-1, and rTNF-beta may contribute individually or in combination to immune-mediated inflammation and tissue injury by stimulating immune adherence of neutrophils to tissue-bound autoantibodies and immune complexes.
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PMID:Recombinant human cytokines stimulate neutrophil adherence to IgG autoantibody-treated epithelial basement membranes. 219 82

In order to clarify the role played by immunologically derived cytokines in dermal connective tissue synthesis and degradation, we investigated the effect of human recombinant (hu-r) interleukin (IL) 1-alpha and beta, hu-r tumor necrosis factor (TNF)-alpha and beta, hu-r IL 2, and hu-r granulocyte-macrophage colony-stimulating factor (GM-CSF) on the production of collagen, glycosaminoglycan, fibronectin, and collagenase activity by three lines of cultured human adult dermal fibroblasts. Our results show that 24-72 h treatment of confluent fibroblast cultures with IL 1-alpha or beta or TNF-alpha or beta causes concentration (1 to 1 X 10(4) U/ml) dependent increases in collagen, glycosaminoglycan, and collagenase activity production, but decreases in fibronectin production. In contrast, treatment with IL 2 and GM-CSF had no effect on fibroblast functions. The data show that IL 1-alpha and beta and TNF-alpha and beta differentially regulate fibroblast functions, and that increases in catabolic functions like collagenase activity production are more than tenfold greater than increases in anabolic functions like collagen production. When these results are considered along with other reports, they suggest that IL 1 and TNF may play predominately a catabolic role in situ during dermal fibrotic responses by directly inhibiting fibronectin production and indirectly causing the degradation of collagen and glycosaminoglycan by significantly increasing dermal fibroblast elaboration of collagenase and proteoglycanase activities.
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PMID:Differential regulation of collagen, glycosaminoglycan, fibronectin, and collagenase activity production in cultured human adult dermal fibroblasts by interleukin 1-alpha and beta and tumor necrosis factor-alpha and beta. 254 Dec 8

Osteoblasts are the cells responsible for the secretion of collagen and ultimately the formation of new bone. These cells have also been shown to regulate osteoclast activity by the secretion of cytokines, which remain to be defined. In an attempt to identify these unknown cytokines, we have induced primary murine osteoblasts with two bone active agents, parathyroid hormone (PTH) and lipopolysaccharide (LPS) and analyzed the conditioned media (CM) for the presence of specific cytokines. Analysis of the CM was accomplished by functional, biochemical, and serological techniques. The data indicate that both PTH and LPS are capable of inducing the osteoblasts to secrete a cytokine, which by all of the techniques used, is indistinguishable from granulocyte-macrophage colony-stimulating factor (GM-CSF). Secretion of GM-CSF is not constitutive and requires active induction. Production of the cytokine is dependent on the dose of PTH or LPS added. It has been demonstrated that the addition of GM-CSF to bone marrow cultures results in the formation of increased numbers of osteoclasts. Therefore, these data suggest that osteoblasts not only participate in bone remodeling by formation of new matrix but may regulate osteoclast activity indirectly by their ability to regulate hematopoiesis.
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PMID:Parathyroid hormone and lipopolysaccharide induce murine osteoblast-like cells to secrete a cytokine indistinguishable from granulocyte-macrophage colony-stimulating factor. 264 17

The x-irradiation biology of supportive stromal cells of the bone marrow microenvironment was investigated by using cloned permanent cell lines that were established from hematopoietically active murine long-term bone marrow cultures. X-irradiation survival curves were derived for each cell line at either 120 cGy/min or clinical low dose rate (LDR) (5 cGy/min) that is used in total body irradiation protocols prior to bone marrow transplantation. Four cell lines, MBA-1, MBA-13, 14F2.1, and D2XRII (Group I) demonstrated a significant increase in D0 at 5 cGy/min (280 cGy, 270 cGy, 210 cGy, and 240 cGy, respectively) compared to 120 cGy/min (215 cGy, 210 cGy, 157 cGy, and 210 cGy, respectively) (p less than 0.05). In contrast, three other clonal cell lines, +/+ #2 cl 4, S1d #3, and GPI alpha-1 (Group II) showed no significant dose rate dependent change in D0 at 5 cGy/min (164 cGy, 174 cGy, and 159 cGy, respectively) compared to 120 cGy/min (159 cGy, 167 cGy, and 143 cGy, respectively). Group I and II cell lines could not be distinguished by differences in synthesis of extracellular matrix proteins including laminin, collagen types I and IV, or histochemically detectable enzymes. Three Group I lines (MBA-1, MBA-13, and D2XRII) and one Group II line, Sld #3, showed decreased support capacity for cocultivated hematopoietic stem cells in vitro. All seven lines had detectable polyA+ mRNA for monocyte colony-stimulating factor (M-CSF) as detected by molecular hybridization; one had detectable levels of polyA+ mRNA for granulocyte-macrophage colony-stimulating factor (GM-CSF) (D2XRII); one, detectable levels of polyA+ mRNA for interleukin 1 (IL-1); and none of the seven had detectable polyA+ mRNA for granulocyte colony-stimulating factor (G-CSF) or IL-3 (multi-CSF). The data indicate that some cells of the hematopoietic microenvironment may not be selectively protected by clinical low dose rate irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Radiosensitivity of cloned permanent murine bone marrow stromal cell lines: nonuniform effect of low dose rate. 304 29

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in pulmonary fibrosis elicited in mice by the intratracheal instillation of bleomycin was investigated by (1) evaluation of GM-CSF mRNA levels, (2) administration of GM-CSF, and (3) administration of anti-GM-CSF antibody. A significant increase of the GM-CSF mRNA level was evident in the lung RNA on day 5 after bleomycin instillation, but not on day 15. Abdominal infusion of GM-CSF (0.5 micrograms/h during days 7-15) did prevent the collagen deposition induced by bleomycin, as measured by the lung hydroxyproline content on day 15. In contrast, anti-GM-CSF antibody markedly aggravated the collagen deposition. On histological sections the proportion of lungs showing fibrosing alveolitis was decreased by GM-CSF and increased by anti-GM-CSF IgG. The percentage and number of macrophages within the bronchoalveolar lavage (BAL) fluid was increased by GM-CSF infusion and decreased by anti-GM-CSF antibodies. This study demonstrates that pulmonary GM-CSF has an inhibitory influence upon the alveolar remodeling and collagen deposition associated with pulmonary fibrosis.
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PMID:Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin. 750 22


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