UNIPROT:P04141 - FACTA Search

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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)

Juvenile myelomonocytic leukemia (JMML) carries a poor prognosis. The endogenous production of cytokines by the JMML cells contributes to their growth and therapeutic resistance. Interleukin (IL)-4, IL-10, and IL-13 inhibit cytokine production in monocytes. We have now studied whether these cytokines can inhibit JMML cell cytokine production, thereby potentially reducing the malignant cell load in this disorder. We found that IL-10, but not IL-4 or IL-13, dose dependently inhibited JMML cell production of the hemopoietic growth factors granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and IL-1beta. Similarly, IL-10, but not IL-4 or IL-13, suppressed JMML colony formation and cell viability. This was not due to the absence of receptors because we could detect mRNAs for the IL-4 and the IL-13 receptor alpha subunits and the IL-2 common gamma subunit in JMML cells. Furthermore, the receptors were active since both IL-4 and IL-13 up-regulated surface expression of MHC class II and down-regulated CD14 antigens on JMML cells and monocytes. Unlike activated monocytes, the JMML cells did not produce IL-10. It is suggested that the loss of cytokine inhibitory effects of IL-4 and IL-13 could play a role in the pathogenesis of this disorder. On the other hand, the inhibition of cytokine production, growth, and viability of JMML cells by IL-10 suggests that this cytokine may have a therapeutic potential in JMML.
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PMID:Interleukin (IL)-10, but not IL-4 or IL-13, inhibits cytokine production and growth in juvenile myelomonocytic leukemia cells. 901 77

Calcitonin gene-related peptide (CGRP) inhibits antigen presentation by Langerhans cells (LC) and macrophages, and LC are anatomically associated with CGRP-containing epidermal nerves. To determine whether CGRP may produce some of its functional effects through regulation of cytokine expression, we utilized enzyme-linked immunosorbent assay (ELISA) of conditioned supernatants to examine production of interleukin (IL)-10 and IL-1 beta protein in the LC-like cell line XS52 as well as the reverse transcriptase-polymerase chain reaction (RT-PCR) to examine levels of mRNA for IL-10, IL-1 beta, and the 40-kDa subunit (p40) of IL-12. CGRP augmented the lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF) -induced release of IL-10 protein and the induced expression of IL-10 mRNA in these cells. However, it suppressed the induction of release of IL-1 beta protein and the induction of mRNA for IL-12 p40 and IL-1 beta by LPS and GM-CSF. Regulation of cytokine expression in peritoneal macrophages was also examined. By ELISA, the LPS-induced expression of IL-10 was augmented by CGRP, whereas the induction of IL-1 beta was suppressed. Northern analysis demonstrated augmentation of LPS-induced IL-10 mRNA levels and inhibition of LPS-induced IL-1 beta mRNA by CGRP. CGRP inhibited the LPS-induced induction of IL-12 mRNA as assessed by RT-PCR. Up-regulation of B7-2 expression by LPS and GM-CSF was suppressed by CGRP in both XS52 cells and macrophages, as previously reported. This suppression, however, could be abrogated by co-culture with neutralizing antibodies to IL-10. Furthermore, the presence of neutralizing antibodies to IL-10 during exposure of epidermal cells (EC) to CGRP prevented the CGRP-mediated suppression of EC presentation of tumor-associated antigens (from the S1509a spindle cell carcinoma) for elicitation of delayed-type hypersensitivity in S1509a-immune mice. These data suggest that suppression of antigen-presenting function by CGRP is mediated, at least in part, by changes in cytokine expression that favor less robust antigen presentation for cell-mediated immunity.
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PMID:Regulation of cytokine expression in macrophages and the Langerhans cell-like line XS52 by calcitonin gene-related peptide. 902 28

The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma on the restoration of impaired TNF-alpha release in LPS-desensitized mice or their refractory macrophages was investigated. Mice pretreated with GM-CSF or IFN-gamma (50 microg/kg i.v.) and injected with 3 mg/kg LPS i.p. displayed increased plasma TNF-alpha levels compared with LPS controls. IL-10 was marginally up-regulated by GM-CSF but abrogated by IFN-gamma pretreatment. LPS-tolerant mice (30 microg/kg LPS i.p., -24 h) showed an attenuated plasma TNF-alpha and IL-10 response to LPS and survived LPS shock. Pretreatment of such mice with GM-CSF or IFN-gamma restored the previously impaired TNF-alpha response. In cultures of murine monocyte/macrophage-containing cell populations, i.e., alveolar, peritoneal, spleen, bone marrow cells, or blood, the presence of GM-CSF or IFN-gamma (10 ng/ml) resulted in an enhanced release of TNF-alpha initiated by 1 microg/ml LPS. Cells from LPS-tolerant mice showed a diminished responsiveness to LPS. However, when exposed to GM-CSF or IFN-gamma ex vivo, their TNF-alpha response to LPS was partially restored. These findings characterize GM-CSF and IFN-gamma as potent enhancers of LPS-induced TNF-alpha production in normal as well as in experimentally immunocompromised mice and provide the rationale for further experiments to explore the pharmacologic use of these cytokines for restoration of immunocompetence in sepsis-associated immunosuppression.
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PMID:Granulocyte-macrophage colony-stimulating factor and IFN-gamma restore the systemic TNF-alpha response to endotoxin in lipopolysaccharide-desensitized mice. 905 23

LPS tolerance is characterized by a diminished monocytic synthesis of TNF-alpha and, interestingly, IL-10 after LPS restimulation. We wondered whether granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, and IFN-gamma can prevent or reverse this down-regulation of TNF-alpha and IL-10 production. The LPS-induced TNF-alpha amounts in desensitized PBMC treated with GM-CSF, IFN-gamma, or IL-12 and in naive, non-cytokine-primed cultures were similar, while much more TNF-alpha was induced in cytokine-primed naive cells. The effect of IL-12 was dependent on the presence of nonmonocytic cells and could be completely blocked with an IFN-gamma antiserum. Treatment of LPS-desensitized pure monocytes with IFN-gamma or GM-CSF resulted in a very high TNF-alpha expression and no difference to cytokine-primed naive monocytes was evident any longer. While IFN-gamma and IL-12 decreased IL-10 expression in naive PBMC, it was increased by both and by GM-CSF in LPS-tolerant cultures. Again, only IL-12 was dependent on the presence of nonmonocytic cells. For prevention of LPS tolerance, similar results were obtained. Recently, we have shown that IL-10 and TGF-beta mediate LPS desensitization in vitro and can be used to establish LPS hyporesponsiveness in the absence of LPS. IFN-gamma and GM-CSF prevented and reversed down-regulation of TNF-alpha and IL-10 synthesis also in the model of IL-10/TGF-beta1-induced LPS hyporesponsiveness, while IL-12 was ineffective because of its obvious inability to induce IFN-gamma. In summary, after LPS desensitization/hyporesponsiveness, IFN-gamma and GM-CSF tended to normalize pro- and anti-inflammatory monocytic behavior. Our results suggest that during LPS desensitization/hyporesponsiveness, monocytes acquire a hitherto unknown functional state with an altered reaction to biologic response modifiers.
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PMID:In vitro prevention and reversal of lipopolysaccharide desensitization by IFN-gamma, IL-12, and granulocyte-macrophage colony-stimulating factor. 905 29

This study was undertaken to investigate the immunomodulatory effect of clarithromycin against synovial fibroblast-like cells (synoviocytes). Synovial tissue obtained from rheumatoid arthritis (RA) or osteoarthritis (OA) patients was enzymatically digested to separate synoviocytes. The synoviocytes were cultured with or without cytokines in the presence of various concentrations of clarithromycin. The expression of costimulatory molecules was examined on the surface of the synoviocytes, using specific MoAbs and flow cytometry. The production of cytokines by synoviocytes was also measured using an immunoenzymatic assay. Finally, autologous T cells were stimulated by interferon-gamma (IFN-gamma)-treated synoviocytes in response to purified protein derivative (PPD). In some experiments, MoAbs specific for costimulatory molecules or clarithromycin were added and 3H-thymidine incorporation was counted. Intercellular adhesion molecule-1 (ICAM-1), LFA-3 and vascular cell adhesion molecule-1 (VCAM-1) were detected on the surface of both RA and OA synoviocytes. However, ICAM-2, B7-1 and B7-2 were not detected, and cytokines failed to induce these molecules. Both spontaneous and up-regulated expression of ICAM-1, LFA-3 and VCAM-1 by IFN-gamma, IL-1beta or 12-o-tetradecanoyl phorbol 13-acetate (TPA) were markedly suppressed by clarithromycin in a dose-dependent manner at concentrations between 0.1 and 10 microg/ml. The production of IL-1beta, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not IL-1alpha and tumour necrosis factor-alpha (TNF-alpha) by synoviocytes was detected. Clarithromycin significantly suppressed the production of these cytokines, but did not enhance IL-10 production. Finally, autologous T cells were stimulated by IFN-gamma-treated synoviocytes in response to PPD. As clarithromycin suppressed HLA-DR and costimulatory molecule expression was enhanced by IFN-gamma, autologous T cell proliferation was markedly inhibited by clarithromycin. Clarithromycin has a considerable immunosuppressive effect on synoviocytes by inhibiting costimulatory molecule expression, cytokine production and antigen-specific T cell proliferation induced by synoviocytes.
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PMID:Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. 909 36

We report here that interleukin-4 (IL-4) induces homotypic aggregation of cultured human mast cells, grown from cord blood mononuclear cells in the presence of stem cell factor and IL-6. This aggregation was specifically induced by IL-4, because other cytokines including IL-1alpha, IL-1beta, IL-2, IL-3, IL-5, IL-9, IL-10, interferon-gamma, IL-12, granulocyte-macrophage colony-stimulating factor, NGF-beta, and tumor necrosis factor-alpha failed to show such effect. Flow cytometric analysis of the cultured mast cells showed that IL-4 increases the expression of lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), but not of very late antigen (VLA) family adhesion molecules or vascular cell adhesion molecule-1 (VCAM-1). Neutralizing monoclonal antibodies specific for LFA-1alpha, LFA-1beta, or ICAM-1 inhibited the IL-4-induced homotypic aggregation of the mast cells, indicating that the aggregation was mediated mainly by LFA-1/ICAM-1 interaction. In addition, IL-4-treated but not untreated mast cells bound to immobilized ICAM-1. This binding was also inhibited by anti-LFA-1 or anti-ICAM-1. These results show that IL-4 promotes expression of ICAM-1 and LFA-1 molecules on mast cells, and suggest that IL-4 may contribute to the migration of mast cells into the inflamed tissue and to the cellular interaction with other inflammatory cells by upregulating adhesion molecules.
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PMID:Interleukin-4 induces homotypic aggregation of human mast cells by promoting LFA-1/ICAM-1 adhesion molecules. 912 35

We compared dendritic cells (DC) derived from CD34+ hematopoietic progenitor cells with tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) to DC derived from monocytes/macrophages with interleukin-4 (IL-4) and GM-CSF. Monocyte/macrophage-derived DC demonstrated higher levels of CD1a, lower levels of CD14, greater stimulatory activity in mixed lymphocyte reactions, and greater capacity to present soluble protein antigen than CD34+ cell-derived DC. Lymphocytes stimulated with antigen-pulsed, monocyte/macrophage-derived DC produced more IL-10 than those stimulated with antigen-pulsed, CD34+-derived DC. Whereas CD1a+ DC could be derived from CD34+ cells in serum-free- and human-sera-containing cultures, the derivation of CD1a+ DC from monocytes/macrophages required the presence of fetal calf serum. The spectrum of cytokine mRNA expression, the presentation of peptide antigen, and the sensitivity to human immunodeficiency virus-1 infection of CD34(+)- and monocyte/macrophage-derived DC were comparable. Although cells derived by both methods are potent antigen-presenting cells, there are differences between DC derived in vitro from hematopoietic progenitors and from monocytes/macrophages that may influence their in vivo activity.
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PMID:Phenotypic and functional differences between human dendritic cells derived in vitro from hematopoietic progenitors and from monocytes/macrophages. 912 9

To investigate the complex intra-articular immune activity in rheumatoid arthritis (RA), we analysed the expression of a wide range of cytokine mRNAs in synovial fluid cells from patients with rheumatoid arthritis. To minimize in vitro artefact, mRNA was rapidly extracted from synovial fluid leucocytes taken from single joints of seven patients and simultaneously from both knee joints of four patients. Expression of interleukin (IL) 1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) was detected using the reverse transcription/polymerase chain reaction. The expression of cytokines varied between patients. IFN-gamma mRNA was detected in 60% of the patients and IL-4 mRNA in 10%. Cytokine expression in both knees was very similar. These results suggest that T-cell activity in RA is detectable using sensitive techniques and that the intra-articular immunopathology of RA is systemically very similar.
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PMID:Symmetrical synovial fluid cell cytokine messenger RNA expression in rheumatoid arthritis: analysis by reverse transcription/polymerase chain reaction. 913 23

Selective accumulation of eosinophils and activated CD4+ cells is now considered a central event in the pathogenesis of asthma, and this process is thought to be mediated by a number of cytokines including tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the Type 2 cytokines interleukin-4 (IL-4) and IL-5. To carry out a detailed time-course analysis of cellular changes in the bronchoalveolar lavage fluid (BAL), peripheral blood (PB), and bone marrow (BM), and of changes in the aforementioned cytokines in BAL and serum, Balb/c mice were sensitized by intraperitoneal injection with ovalbumin (OVA) adsorbed to aluminum hydroxide on two occasions 5 days apart, and were subjected to an OVA aerosol challenge 12 days after the second sensitization. This resulted in an airways inflammatory response characterized by early transient neutrophilia, marked eosinophilia, and, to a lesser extent, lymphocytosis in the BAL. Inflammatory events were first observed 3 h and 24 h after antigen challenge in the lung tissue and BAL, respectively, and lasted for 21 days. In the BM, we detected a 1.5- and 5-fold increase in the total number of cells and eosinophils, respectively, 4 days after the second sensitization. This was followed by a decrease, although BM eosinophilia remained clearly present at the time of antigen challenge. A second eosinopoietic event was observed in the BM shortly after challenge and reached a peak at day 3. BM cellularity returned to normal at day 21 after challenge. Serum OVA-specific IgE was first detected 3 days following the second sensitization (150 ng/ml). IgE levels then decreased but remained at the 75 ng/ml range at the time of the aerosol challenge. During the sensitization period, TNF-alpha (approximately 25 pg/ml), IL-4 (approximately 40 pg/ml), and IL-5 (approximately 250 pg/ml) were detected in serum, but not in the BAL fluid (BALF) and returned to background levels at the time of the antigen challenge. After antigen challenge, TNF-alpha, IL-4, IL-5, and GM-CSF were detected in serum. Peak levels were observed at 3 h (approximately 40 pg/ml), 3 h (approximately 120 pg/ml), 12 h (approximately 350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, and returned to background levels 24 h after challenge. In the BALF, we detected peak levels of TNF-alpha, IL-4, IL-5, and GM-CSF at 6 h (approximately 250 pg/ml), 24 h (approximately 140 pg/ml), 24 h (350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, with a return to background levels 5 days after challenge. No IL-10 could be detected at any time point during sensitization or after challenge in either serum or BAL. We also detected approximately 40 pg/ml of interferon-gamma (IFN-gamma) in the serum of normal untreated mice. Serum IFN-gamma levels fluctuated during sensitization and after challenge, but never exceeded those observed in untreated mice. Thus, the cytokine profile observed in this experimental model of allergic inflammation is characterized by IL-4 and IL-5 dominance, with an apparently minor TNF-alpha and GM-CSF contribution and relatively low or undetectable levels of IFN-gamma and IL-10.
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PMID:Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. 916 Aug 31

Expression of the two myeloic related proteins MRP8 and MRP14 is restricted to distinct stages of monocytic differentiation. Heterodimeric MRP8/14 complexes (27E10 antigen) have been shown to represent their biologically active forms. In this study, we investigated the effects of Th2-cytokines on release of these proteins from freshly obtained blood monocytes and monocytes cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocytes were stimulated with pokeweed mitogen (PWM) in the presence or absence of interleukin-13 (IL-13), IL-4 and IL-10, and secretion of MRP8, MRP14 and MRP8/14 was assessed by using a sandwich enzyme-linked immunosorbent assay system. Peripheral monocytes secreted significantly increased amounts of MRP14 and MRP8/14 but not MRP8 under stimulation with PWM. IL-10 and IL-4, but not IL-13, down-regulated the PWM-stimulated MRP8/14 secretion in a dose-dependent manner. Maximal inhibition required that IL-10 and IL-4 be added up to 1 h before or simultaneous with PWM. A combination of IL-10 and IL-4 even at suboptimal concentrations significantly suppressed protein secretion much more than using IL-10 or IL-4 at a doubled concentration alone. Peripheral monocytes cultured for 7 days in the presence of GM-CSF showed two-to threefold higher protein levels compared with freshly obtained blood monocytes but responded inefficiently to either IL-4, IL-13, or IL-10 alone. However, treatment with IL-10 in combination with IL-4 but not IL-13 strongly suppressed MRP14 and MRP8/14 release by these cells. The unresponsiveness of 7-day-cultured blood macrophages suggests that more differentiated and activated cells may lose their ability to respond to anti-inflammatory cytokines. Combined cytokine treatment may therefore more effectively control the progression of chronic inflammatory processes.
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PMID:Importance of combined treatment with IL-10 and IL-4, but not IL-13, for inhibition of monocyte release of the Ca(2+)-binding protein MRP8/14. 920 76

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