Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine release at the cartilage/pannus junction (CPJ) may be involved in cartilage destruction and tissue repair in rheumatoid arthritis (RA). Tissue samples of CPJ from 12 RA patients were examined for the presence of cytokines using immunohistochemical techniques with immunoaffinity purified F(ab')2 antibodies raised against recombinant human cytokines. Twenty-four areas of distinct CPJ at which a discrete junction between cartilage and overlying pannus exists were observed. In all specimens, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-beta 1 were detected in cells in pannus particularly along the surface of cartilage and at the site of cartilage erosion. Double immunofluorescence staining showed that most cytokine containing cells also labelled with a macrophage marker (CD68). About 50% of blood vessel endothelial cells stained for GM-CSF. Twelve areas of diffuse fibroblastic CPJ, at which an indistinct margin is seen between cartilage and pannus were examined. At this site, TGF-beta 1 was the only cytokine detected in fibroblast-like cells. None of these cytokines were detected in synovial tissue at the normal synovium/cartilage junction. Chondrocytes from all 11 normal specimens as well as those from RA patients stained for IL-1 alpha, TNF-alpha, IL-6, GM-CSF and TGF-beta 1, especially those close to subchondral bone. However, IL-1 beta, interferon-gamma and lymphotoxin were not detected in either the normal synovium/cartilage junction or rheumatoid CPJ.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. 139 70

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.
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PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

Transforming growth factor-beta (TGF-beta) is a family of polypeptide growth factors with multiple functional activities. Recent studies suggest that TGF-beta is a selective inhibitor of hematopoietic cells. In this report, we study the effect of TGF-beta 1 on the proliferation of murine peritoneal exudate macrophages (PEM) in response to purified murine recombinant granulocyte-macrophage colony-stimulating factor (rMuGM-CSF) and human recombinant M-CSF (rHuM-CSF). In mice, PEM and other types of tissue macrophages display multiple types of receptors for CSFs and respond to them, either alone or in combination, to undergo extensive proliferation in vitro. Recombinant human TGF-beta 1 (rHuTGF-beta 1) (0.1 to 1.0 ng/mL) markedly enhanced the growth of PEM in response to rMuGM-CSF but inhibited their responsiveness to rHuM-CSF. Similar effects of rHuTGF-beta 1 were also detected using murine pulmonary alveolar macrophages (PAM) and bone marrow-derived macrophages (BMDM). Receptor binding assays using iodinated rMuGM-CSF and rHuM-CSF showed that rHuTGF-beta 1 treatment greatly enhanced the expression of GM-CSF receptors in PEM, in a time- and dose-dependent manner, suggesting a possible mechanism for the synergistic effect of TGF-beta 1. On the other hand, the expression of M-CSF receptors was not affected by TGF-beta 1 treatment. Analysis by mRNA PCR showed that the synergistic effect of TGF-beta 1 is not due to autocrine CSFs produced by treated cells. Our results suggest that TGF-beta 1 is an important regulator of macrophage proliferation. Depending on the types of CSFs present, TGF-beta 1 may act either as a growth promoter or inhibitor.
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PMID:Transforming growth factor-beta 1 bifunctionally regulates murine macrophage proliferation. 153 54

Transforming growth factor-beta (TGF-beta) has potent antiproliferative effects on human hematopoietic progenitor cells. We report here that TGF-beta 1 and -beta 2 also exert bimodal dose-dependent stimulation of granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte-CSF-induced day 7 granulocyte-macrophage colony-forming units. This increase in colony formation was restricted to low doses (0.01 to 1.0 ng/mL) of TGF-beta 1 and was due to increased granulopoiesis, showing that TGF-beta can affect the differentiation as well as the proliferation of hematopoietic progenitors. Furthermore, TGF-beta 3 was found to be a more potent inhibitor of hematopoietic progenitor cells than TGF-beta 1 and -beta 2. In contrast to the bidirectional proliferative effects of TGF-beta 1 and -beta 2, the effects of TGF-beta 3 on human hematopoiesis were only inhibitory, showing for the first time that TGF-beta isoforms differ not only in potencies but also with regard to the nature of the response they elicit.
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PMID:Bidirectional effects of transforming growth factor beta (TGF-beta) on colony-stimulating factor-induced human myelopoiesis in vitro: differential effects of distinct TGF-beta isoforms. 171 92

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

In this paper, the in vitro growth of bone marrow early (megakaryocyte burst-forming units, BFU-meg) and late (megakaryocyte colony-forming units, CFU-meg) progenitors was evaluated in 18 essential thrombocythemia (ET) patients and 22 normal control subjects. BFU-meg clonality was demonstrated both in normal and ET bone marrows, cultivating these primitive progenitors at limiting dilutions in plasma clot assay: 1 to 7 BFU-meg/2.5 x 10(4) mononuclear non-adherent cells were observed, with a strong correlation in ET [r = 0.955 stimulated by recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) plus recombinant human interleukin (rhIL) 3], as well as in normal controls (r = 0.969). In order to clearly elucidate the in vitro response of ET megakaryocyte (meg) progenitors to recombinant growth factors, the interference of accessory cells (i.e., monocytes, T lymphocytes, and natural killer cells) and human serum were avoided by performing experiments on CD34+ cells in a serum-free fibrin clot assay. The number of both early and late meg progenitors in ET was significantly increased in response to rhIL-3, rhIL-3 plus rhIL-6, and rhIL-3 plus rhGM-CSF, but not in response to rhGM-CSF alone. Furthermore, both meg progenitors were investigated for their response to rh transfer growth factor (TGF)-beta 1, tested at concentrations from 0.01 to 10 ng/ml. rhTGF-beta 1 was able to inhibit CFU-meg and BFU-meg in a dose-response manner normal, whereas ET CFU-meg appeared less sensitive to the lower doses investigated (p less than 0.05) and ET BFU-meg were slightly reduced in number only at the higher concentrations of rhTGF-beta 1 (p less than 0.01). Our data suggest that the increased thrombopoiesis in ET may depend on an increased sensitivity of meg progenitors to some of the physiological growth factors and to a disrupted sensitivity to at least one negative regulator of megakaryocytopoiesis. Since these abnormalities involve both meg progenitors, this can be considered a demonstration that the neoplastic event hits the most primitive hemopoietic progenitors.
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PMID:Essential thrombocythemia: impaired regulation of megakaryocyte progenitors. 201 Jun 54

The supernatant of unstimulated purified NKH-1 bearing human natural killer (NK) cells was found to enhance ongoing immunoglobulin synthesis. This NK-Cell supernatant (NKSN) enhanced IgE, IgG, and IgA synthesis from corresponding B-cell lines without increasing thymidine incorporation or cell number. Separation of NKH-1+ cells into CD3- or CD3+ cells showed that this activity was produced by the CD3- population. Recombinant human interleukin (IL)-1, IL-2, IL-4, interferon (INF)-beta 1, INF-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, or partially purified low molecular weight B-cell growth factor (BCGF) failed to provide the same enhancement of Ig synthesis. While the NKSN contained small amounts of IL-6 (0.1 U/ml) and IL-6 could increase Ig synthesis in vitro, the optimal IL-6 enhancement was far less than that observed with NKSN. NKSN also enhanced ongoing Ig synthesis from in vivo activated B cells obtained from peripheral blood or bone marrow but failed to induce Ig synthesis from resting or in vitro activated B cells. These results demonstrate that human NK (CD3-, NKH-1+) cells can produce B-cell differentiation activity capable of regulating Ig production in vivo, which appears to be distinct from the activity of previously described cytokines.
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PMID:Human natural killer (NK) cells produce a late-acting B-cell differentiation activity. 326 82

The effects of transforming growth factor (TGF) beta 1 on cytokine-enhanced eosinophil survival and degranulation were investigated in vitro to determine whether it is an inhibitory regulator of allergic inflammation. Peripheral blood eosinophils purified by Percoll density gradient centrifugation and the CD16 negative selection technique were incubated in the presence of eosinophil-activating cytokines (interleukin-5 (IL-5), IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma) with and without TFG-beta 1 for 1-3 days. On day 1, eosinophil protein X release was measured by radioimmunoassay. Eosinophil viability on day 3 was determined by staining the cells with fluorescein diacetate and propidium iodide, and on the same day DNA was extracted and subjected to gel electrophoresis to test for fragmentation. TGF-beta 1 significantly inhibited eosinophil survival enhanced by IL-5, IL-3, GM-CSF and IFN-gamma in a dose-dependent manner. The inhibitory effects of TGF-beta 1 on IL-5-enhanced survival was partially reversed by high concentrations of IL-5 and was completely neutralized with anti-TGF-beta antibody. IL-5 inhibited DNA fragmentation of eosinophils in vitro. TGF-beta reversed the effect of IL-5, indicating that TGF-beta 1 activates the pathway of apoptosis. TGF-beta 1 significantly suppressed eosinophil protein X release induced by IL-5. These results suggest that TGF-beta 1 may play a role in the modulation of allergic inflammation.
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PMID:Inhibitory effect of transforming growth factor beta 1 on cytokine-enhanced eosinophil survival and degranulation. 754 18

Complement biosynthesis in monocytes is stimulated by different pathogens and modulated by a variety of cytokines, but little is known about the possible effect of transforming growth factor beta (TGF-beta) on this monocyte function. We therefore studied the effect of TGF-beta 1 and TGF-beta 2 on constitutive, lipopolysaccharide (LPS)- and Candida albicans-induced monocyte biosynthesis of complement components C3 and factor B. Under all three conditions, both forms of TGF-beta (20 ng/ml) induced a two- to fourfold increase in C3 concentration in monocyte supernatants harvested after 2 or 5 days of cell culture, an effect that was abrogated by cycloheximide. In contrast, constitutive and pathogen-induced production of factor B was suppressed by TGF-beta. The effects of TGF-beta on complement production were neutralized by a monoclonal anti-TGF-beta antibody. Moreover, TGF-beta suppressed the pathogen-induced release of granulocyte-macrophage colony-stimulating factor and down-regulated the expression of complement receptor 3 (CD11b/CD18), while the expression of CD11a/CD18, a related beta 2 integrin, was unaffected. These novel effects of TGF-beta emphasize the immunomodulatory significance of this cytokine.
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PMID:Transforming growth factor beta modulates C3 and factor B biosynthesis and complement receptor 3 expression in cultured human monocytes. 785 44

Eosinophils interact with extracellular matrix proteins and endothelial cells through adhesion proteins belonging to the beta 1 and beta 2 subfamilies of integrins. Extending previous observations, we found that tumour necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor stimulated generation of superoxide anion by eosinophils plated on fibronectin-coated surfaces. As studies with adherent neutrophils indicated that TNF might act as activating leucocyte integrins to deliver signals involved in activation of cell functions, we investigated the effects of monoclonal antibodies (mAb) directed against VLA-4 (CD49d/CD29), LFA-1 (CD11a/CD18), CR3 (CD11b/CD18) or the common beta 2 subunit (CD18) on generation of eosinophil toxic oxygen molecules and spreading. We show that cross-linking of members of both the beta 1 and the beta 2 integrin subfamilies triggers eosinophil respiratory burst and spreading. Evidence for the selectivity of anti-integrin mAb effects is derived from the findings that isotype-matched mAb of other specificities (anti-class I MHC Ag, anti-beta 2-microglobulin, anti-CD4) did not trigger eosinophil functions. The findings presented in this paper suggest that integrin-dependent, eosinophil adhesion in sites of allergic reaction may be accompanied by release of toxic oxygen molecules involved in tissue damage.
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PMID:Ligation of members of the beta 1 or the beta 2 subfamilies of integrins by antibodies triggers eosinophil respiratory burst and spreading. 790 78


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