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)

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.
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PMID:Cytokines in autoimmunity. 146 99

Large quantities of human blood-derived monocytes have been cultured in suspension in nonadherent cell culture bags and maintained for up to 3 weeks in a serum-free medium. This serum-free medium contained Iscove's modified Dulbecco's medium (IMDM) supplemented with human albumin, alpha-phosphatidylcholine, transferrin, and insulin. Morphology, cell surface antigens, and functional properties of these in vitro maturing macrophages were studied in comparison with macrophages cultured in a standard medium containing 10% fetal calf serum. In this report we demonstrate that this serum-free medium allows a better yield of cell survival than the standard medium; it also allows the differentiation of blood monocytes into fully functional macrophagic cells that express the different antigens found in mature macrophages. The results indicate that the use of serum-free defined medium offers good conditions in which to culture large numbers of human monocytes and allows an accurate analysis of the effect of supplementation with growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on the differentiation and survival of monocytes and macrophages. Serum-free cultures could also be helpful for the precise analysis of the cell secretion activity and for determining the factors that are responsible for monocyte maturation into macrophages.
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PMID:Human blood-derived macrophages: differentiation in vitro of a large quantity of cells in serum-free medium. 157 91

Although under study to alleviate chemotherapy-induced bone marrow toxicity, cytokines can stimulate in vitro growth of solid human tumour cell lines. The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) on in vitro colony formation of primary human tumours was studied in a capillary soft-agar cloning system. Of 108 tumour specimens from 100 patients, 85 specimens were tested against all three factors at concentrations ranging from 0.1 to 1000 ng/ml. 44 of 100 tumours showed adequate growth in controls. 8 out of 43 (19%) specimens were significantly stimulated by GM-CSF, 6 of 40 (15%) by G-CSF and 10 of 44 (23%) by IL-3. Sensitivity to all three cytokines was observed in 4 of 44 (9%) specimens. By light microscopy the appearance of colonies from stimulated specimens was identical to that of controls. Sensitivity to cytokines was independent from sensitivity to epidermal growth factor, transferrin or insulin. Sensitivity to GM-CSF, G-CSF and IL-3 may be aberrantly expressed in a subgroup of solid human tumours.
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PMID:Effects of cytokines on in vitro colony formation of primary human tumour specimens. 170 19

Colony-stimulating factor-1 (CSF-1 or M-CSF) supports the proliferation and survival of mononuclear phagocytes by binding to a receptor (CSF-1R) encoded by the c-fms proto-oncogene. Whereas the CSF-1R kinase is normally regulated by ligand, receptors bearing 'activating mutations' act constitutively as enzymes and can transform fibroblasts and haemopoietic cells of different lineages. Introduction of human CSF-1R enables mouse NIH-3T3 cells to form colonies in agar in response to human CSF-1 and to proliferate in serum-free medium supplemented with CSF-1, albumin, transferrin and insulin. Similarly, expression of human CSF-1R in interleukin 3-dependent mouse FDC-P1 myeloid cells enables them to grow in CSF-1. High levels of CSF-1R expression in FDC-P1 cells can induce factor-independent growth which is abrogated by a 'neutralizing' monoclonal antibody to the receptor. Therefore, critical mutations in the c-fms gene or overexpression of CSF-1R in immature myeloid precursors might each contribute to leukaemia.
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PMID:Signal-response coupling mediated by the transduced colony-stimulating factor-1 receptor and its oncogenic fms variants in naive cells. 215 60

The ability of malignant cells to respond to growth factor(s) present in or secreted by a distant target organ may be important in tumor metastasis. We used metastatic cell lines and clones of the rat 13762NF mammary adenocarcinoma that show reproducible spontaneous metastatic behavior from the mammary fat pad to regional lymph nodes and lung sites. Whereas poorly lung metastatic MTPa and MTC cells did not grow in response to lung-conditioned medium, highly lung-metastatic MTLn3 cells responded and grew rapidly in lung-conditioned medium. The major growth-promoting factor for MTLn3 cells from porcine and rat lung-conditioned media was purified by using hydroxylapatite affinity and anion exchange chromatography, chromatofocusing, size exclusion chromatography, and preparative native gel electrophoresis. The activity in each of the purification fractions was measured by determining their ability to increase the number of MTLn3 cells in serum-deprived culture. The major component that differentially stimulated the growth of highly metastatic MTLn3 cells was a glycoprotein of Mr approximately 66,000. Under reducing conditions, its apparent Mr was approximately 72,000. This lung-derived mitogen was stable at pH 4.0-9.0, possessed a pI of 6.9-7.0, and preferentially promoted the growth of lung-metastasizing tumor lines over their poorly lung-metastasizing counterparts in rat 13762NF mammary adenocarcinoma and murine B16 melanoma tumor systems. The activity of porcine lung-derived growth factor was not affected by pretreatment with antisera to porcine insulin, human granulocyte-macrophage colony-stimulating factor, human platelet-derived growth factor, or murine epidermal growth factor. It was inactivated by reduction with dithiothreitol or exposure to high temperature (95 degrees C). The results suggest that specific organ-derived growth factors are important in metastatic colonization and organ growth of particular malignant cells.
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PMID:Purification and some properties of a lung-derived growth factor that differentially stimulates the growth of tumor cells metastatic to the lung. 254 64

We demonstrated that 125I-labeled human parathyroid hormone (1-34;8,18-Nle,34-Tyr)[[125I]hPTH(1-34)] bound specifically to hemopoietic blast cells supported by granulocyte-macrophage colony-stimulating factor. Half-maximal inhibition of binding was achieved at concentrations of unlabeled hPTH(1-34) of about 5 x 10(-9)M. Insulin and hPTH(39-68) did not compete for PTH binding sites. Specific binding of hPTH(1-34) was detected in neither macrophages nor multinucleated cells (MNC's). Furthermore, treatment of hemopoietic blast cells with hPTH(1-34) stimulated MNC formation, and the range of concentrations (10(-10)-10(-8)M) over which hPTH(1-34) caused these effects was similar to that which inhibited the binding of [125I]hPTH(1-34). These findings suggest the presence of a PTH receptor on osteoclast precursors and the direct effect of PTH on them, resulting in osteoclast-mediated bone resorption.
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PMID:Existence of parathyroid hormone binding sites on murine hemopoietic blast cells. 255 Dec 92

Human cord blood progenitor-derived erythroblasts have recently been shown to respond to erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF) with a transient increase in intracellular free calcium concentration [Cac]. However, the importance of [Cac] changes in mediating cell proliferation and/or differentiation is undefined. In the present study, the response of erythroid precursors at different stages of differentiation to Epo was examined. Erythroblasts were derived from adult blood erythroid progenitors (BFU-E) at day 7 or day 10 of culture. [Cac] was measured in individual Fura-2 loaded cells with fluorescence microscopy coupled digital video imaging. The dynamic range (Rmax/Rmin) of intracellular Fura-2 was similar to that measured in free solution, suggesting insignificant amounts of intracellular Ca insensitive forms of Fura-2. Baseline [Cac] of erythroid cells calculated with an in vitro calibration method was 44 +/- 4 nmol/L and with an in vivo method was 46 +/- 4 nmol/L. Treatment of day 7 BFU-E derived erythroblasts with Epo resulted in no significant increase in [Cac]. In contrast, in more mature erythroblasts (day 10 of culture), Epo stimulated a large increase in [Cac] from 49 +/- 11 nmol/L at baseline to 279 +/- 47 nmol/L. This [Cac] increase occurred in phosphate buffered saline (PBS) containing no added calcium. The increase in [Cac] persisted for 18 minutes and was dose dependent. Day 7 and day 10 control cells treated with either insulin or media showed no significant change in [Cac] during 18 minutes of observation. Our data demonstrate that early (day 7) and late (day 10) erythroblasts display different responses to Epo, at least in terms of intracellular Ca++ fluxes. The differential [Cac] response observed in early and late erythroid precursors to growth factor stimulation suggests that [Cac] may be an important signal in cell differentiation.
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PMID:Erythropoietin stimulates a rise in intracellular-free calcium concentration in single BFU-E derived erythroblasts at specific stages of differentiation. 264 70

The presence of heterogeneous erythroid progenitor cells, contaminant cells, or serum may alter erythroid colony development in vitro. To obtain highly purified colony-forming units-erythroid (CFU-E), we cultured partially purified human blood burst-forming units-erythroid (BFU-E) in methylcellulose with recombinant human erythropoietin (rHuEPO) for 7 d and generated cells that consisted of 30-60% CFU-E, but no BFU-E. A serum-free medium was used that allowed development of the same number of erythroid colonies as serum containing medium, but with a greater percentage of larger colonies. This medium consisted of delipidated crystalline bovine serum albumin, iron saturated transferrin, lipid suspension, fibrinogen, thrombin, Iscove's modified Dulbecco's medium/F-12[HAM], and insulin plus rHuEPO. When CFU-E were cultured in a limiting dilution assay and the percentage of nonresponder wells was plotted against cell concentration, both serum-free cultures and serum-containing cultures yielded overlapping straight lines through the origin indicating that CFU-E development did not depend on accessory cells and that insulin acted directly on the CFU-E. Human recombinant interleukin 3 (IL-3) and/or granulocyte-macrophage colony-stimulating factor had no effect on CFU-E growth, while they markedly enhanced BFU-E growth. Physiological concentrations of recombinant human insulin-like growth factor I (IGF-I) enhanced CFU-E growth in the absence of insulin and, together with rHuEPO in serum-free medium, provided a plating efficiency equal to that of serum-containing medium. Limiting dilution analysis in serum-free medium with IGF-I showed a straight line through the origin indicating that IGF-I also acted directly on the CFU-E and not through an effect on accessory cells. These data demonstrate that CFU-E do not require accessory cells, but do require IGF-I and/or insulin which act directly on the CFU-E.
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PMID:Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development. 265 78

Presented are the steps in creating a recombinant DNA molecule, examples of recombinant drug products, a description of DNA fingerprinting methods for diagnosing diseases, a discussion of the patenting of recombinant drugs, and a look to the future of this revolutionary biotechnology. Constructing a recombinant DNA molecule involves cutting the DNA into fragments with restriction endonucleases and rejoining the fragments in novel arrangements with ligase. Propagating the molecule in a microorganism, or cloning, is necessary to increase the number of gene copies to facilitate detection of the gene of interest and to produce the protein it encodes. Recombinant DNA drug products have been developed that represent the communicator, structural, and modifier classes of proteins. Recombinant communicator proteins include interferons alfa-2a and alfa-2b and granulocyte-macrophage colony-stimulating factor (immune system modulators); epidermal growth factor and erythropoietin (tissue repair promoters); and human insulin, growth hormone, and atrial peptide (metabolism modulators). Recombinant structural proteins include hepatitis B virus vaccine and CD4 protein, and recombinant modifier proteins include tissue plasminogen activator and superoxide dismutase (agents that split or splice organic molecules). In the future, gene defects associated with genetic diseases will be unraveled, leading to the production of new therapeutic agents designed to counteract or actually reverse those defects. Recombinant protein drugs will be further tailored to enhance their activity and specificity. These advances are so novel and momentous that patent protection has been extended not only to recombinant drugs but to the recombinant microorganisms in which they are manufactured. In cloning genes, investigators directly use the protein designs that occur naturally. Basic research will soon lead to the engineering of novel proteins with specified functions.
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PMID:Drug products of recombinant DNA technology. 267 63

We previously reported that administration of a streptococcal preparation (OK-432) inhibited insulitis and development of autoimmune diabetes in nonobese diabetic (NOD) mice and BB rats as animals models of insulin-dependent diabetes mellitus. In this study, we screened various cytokines that could be induced by OK-432 in vivo, for their preventive effect against diabetes in NOD mice. Among recombinant mouse IFN gamma, human IL1 alpha, human IL2, mouse granulocyte-macrophage colony-stimulating factor and human TNF alpha, only human TNF alpha suppressed insulitis and significantly (P less than 0.001) inhibited development of diabetes. NOD mice were the lowest producers of the mRNA of TNF and serum TNF on stimulation with OK-432 or with IFN gamma plus LPS, compared with C57BL/6, C3H/He, and Balb/c mice. The results imply a role for low productivity of TNF in the pathogenesis of autoimmune diabetes in NOD mice.
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PMID:Recombinant human tumor necrosis factor alpha suppresses autoimmune diabetes in nonobese diabetic mice. 279 65


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