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)

Human peripheral blood leukocytes (hPBL) are a rich source of natural leukocyte interferon (IFN-alpha) when treated with Sendai virus. Sendai virus treatment of hPBL will also result in significant production of several chemokines and cytokines such as macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, RANTES, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-8, in a time-dependent way. A significant amount of MCP-1 is constitutively produced in overnight culture of leukocytes. The most abundant cytokine is IFN-alpha, which is induced to its maximum level approximately 11-15 h after addition of Sendai virus. The amount of IFN-alpha induced at 15 h after Sendai virus treatment is more than 16-fold higher than those of MIP-1alpha, MIP-1beta, and RANTES. IFN-alpha is also induced more than 60-fold higher than TNF-alpha and IL-8. The amount of IL-6 induced is approximately 400-fold less than IFN-alpha. Limited amounts of other cytokines such as IL-1alpha, IL-1beta, macrophage colony-stimulating factor, TNF-beta, and IFN-gamma are also induced in Sendai virus-treated hPBL. No measurable amount of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, leukemia inhibitory factor, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-11, or IL-12 was induced in the supernatant of Sendai virus-treated hPBL.
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PMID:Cytokines induced by Sendai virus in human peripheral blood leukocytes. 869 16

Freshly excised human head and neck cancers (219 primary cancers; 64 metastatic lymph node cancers) were analyzed for the immune inhibitory mediators released from the cancer tissues and the immune infiltrate within the tumor. Significant levels of the immune inhibitory mediators transforming growth factor-beta (TGF-beta), prostaglandin E2 (PGE2) and interleukin-10 (IL-10) were released from these cancers. Also released was granulocyte-macrophage colony-stimulating factor (GM-CSF), whose secretion was associated with an intratumoral presence of CD34+ cells. We have previously shown that CD34+ cells within human head and neck cancers are immune inhibitory granulocyte-macrophage progenitor cells. The presence of TGF-beta, PGE2 and IL-10 was associated with a reduced content of CD8+ T-cells within the cancers. The CD4+ cell content appeared to be less affected by these immune inhibitory mediators. Instead, parameters indicative of CD4+ cell function (p55 IL-2 receptor expression, release of IL-2 and IFN-gamma) were diminished in cancers that released higher levels of TGF-beta, IL-10 and GM-CSF and had a higher CD34+ cell content. Furthermore, metastatic cancers released higher levels of the soluble immune inhibitory mediators and lower levels of IFN-gamma and IL-2 than did primary cancers, although CD34+ cells were similarly present in both primary and metastatic cancers. Our results show that human head and neck cancers have a multiplicity of non-mutually exclusive mechanisms of immune suppression that are most prominently associated with reduced CD8+ cell influx and reduced influx and altered function of intratumoral CD4+ cells.
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PMID:Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. 870 5

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector MFG-granulocyte-macrophage colony-stimulating factor (GM-CSF), to examine immune stimulation conferred by localized GM-CSF production. Expression of murine GM-CSF by neuro-2a (N-2a/GM) significantly reduced its tumorigenicity. Moreover, immunization of mice with irradiated N-2a/GM cells resulted in a significant protective effect against live tumor challenge 14 days later. Approximately 41% of mice immunized with irradiated N-2a/GM versus 0% of those vaccinated with irradiated parental tumor survived. Surviving mice were rechallenged after 50 days with wild-type neuro-2a or with the Sa1 syngeneic sarcoma to discern whether the generated immunity was durable and tumor specific. All mice survived wild-type neuro-2a challenge, whereas none survived inoculation with Sa1. Because both CD4+ and CD8+ T cells were necessary during priming to this MHC class Ilo, II-tumor, these data indicate that major histocompatibility complex (MHC) class I+, II+ antigen-presenting cells (APCs) were required for the T-cell antitumor response. Co-expression of GM-CSF and IFN-gamma, both of which have immunostimulatory activities on antigen-presenting cells, abrogated the tumorigenic potential of this tumor and increased immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of mice with preexisting retroperitoneal tumors with irradiated N-2a/GM and irradiated N-2a/IFN/GM improved survival. There was a trend for nonirradiated transduced cells to be more immunogenic than their irradiated counterparts. Immunohistochemistry of tissues from the vaccination site revealed a pronounced macrophage infiltration associated with nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that vaccination involving nonirradiated neuroblastoma cells transduced with genes that stimulate APCs may be a useful approach in stimulating antitumor T-cell responses.
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PMID:Effective immunization against neuroblastoma using double-transduced tumor cells secreting GM-CSF and interferon-gamma. 873 94

Platelets and megakaryocytes express Fc receptors for IgG which are encoded by the Fc gamma RIIA gene. In an effort to establish a cellular model for induction of Fc gamma RIIA expression during megakaryocyte development by hematopoietic growth factors, steady-state Fc gamma RIIA mRNA levels were monitored in c-kit receptor-positive megakaryocytic cells (M07e, HEL, and Dami) in response to c-kit ligand (KL; also known as stem cell factor, mast cell growth factor, or Steel factor). Northern blot analysis showed that exposure of cells to KL led to significant increases in Fc gamma RIIA levels in M07e (15 x at 24 hours), with smaller increases in HEL (1.9 x at 2 hours) and Dami (1.6 x at 24 hours) cells. K562 cells, which lack c-kit receptor, showed no effect of KL on modulating Fc gamma RIIA mRNA levels. The effects of KL were specific for Fc gamma RIIA, as there were no effects on platelet factor 4 (PF4), gamma-globin, or GATA-1 mRNA levels. Effects of KL, alone and in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and gamma-interferon (IFN-gamma), on surface Fc gamma RIIA expression were assessed by flow cytometry using anti-Fc gamma RII monoclonal antibody IV.3. In M07e cells, KL alone and in combination led to significant increases in the percentage of cells positive for surface Fc gamma RIIA and the mean cell fluorescence intensity. Transient transfection studies of an Fc gamma RIIA promoter-luciferase reporter gene in the presence or absence of KL showed increased reporter gene expression in KL-treated cells, with the largest increase (3.7-fold) in the M07e cells. In HEL and Dami cells, other cytokines active in megakaryocytopoiesis when used alone (interleukin-3 [IL-3], IL-6, IL-11, GM-CSF) had negligible activity in increasing reporter gene activity. These results suggest that increased levels of Fc gamma RIIA mRNA after KL treatment of M07e cells are a result, in part, of increased Fc gamma RIIA gene transcription. Our results indicate that M07e cells represent a cellular model for KL-induced Fc gamma RIIA expression in early megakaryocyte development.
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PMID:Human c-kit ligand (stem cell factor) induces platelet Fc receptor expression in megakaryoblastic cells. 876 99

We provide a model for induction of T cell-independent, polysaccharide-specific Ig secretion in response to bacterial challenge. Two predominant pathways are defined that require the concerted action of multivalent membrane Ig cross-linking by the polysaccharide Ag with 1) various B cell-activating moieties contained within the bacterial pathogen and/or 2) cytokines, such as IFN-gamma and granulocyte-macrophage colony-stimulating factor produced by NK cells and macrophages, that become activated in a T cell-independent manner during bacterial infection.
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PMID:A model for induction of T cell-independent humoral immunity in response to polysaccharide antigens. 880 17

Monocytes/macrophages are efficient producers of alpha interferons (IFN), and IFN-gamma is a potent activator of these cells. The present study sought to investigate whether IFN-alpha affects the capacity of human monocytes/macrophages to produce IFN-alpha on induction with Sendai virus. Plastic-adherent human peripheral blood monocytes were grown in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) for 3 weeks during which they were transformed into macrophages. At various times, the cultures were pretreated for 24 h with IFN-gamma and induced with Sendai virus for IFN-alpha production. Pretreatment with IFN-gamma had no effect on the production of IFN-alpha during the first days in culture. The production of IFN-alpha was thereafter significantly enhanced by the IFN-gamma pretreatment. Minute amounts of IFN-gamma, < or = 0.1 IU/ml, increased the production of IFN-alpha in macrophages cultured for more than 7 days. The cooperation between IFN-gamma and IFN-alpha in macrophages may play a role in the antiviral defense of the body.
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PMID:IFN-gamma enhances production of IFN-alpha in human macrophages but not in monocytes. 880

Human CD38, a surface glycoprotein expressed by different immunocompetent cells, is associated with distinct transmembrane signaling molecules and plays a key role in the synthesis of cyclic ADP-ribose, a calcium-mobilizing compound. This study reports that CD38 ligation by specific monoclonal antibodies (mAb) in purified peripheral blood T cells is followed by secretion of discrete cytokines. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-gamma, and IL-10 mRNA expression were constant findings. Low levels of IL-2 mRNA were also detected in CD38-activated T lymphocyte cultures of all subjects studied. Low levels of IL-4 and IL-5 mRNA were detected in the majority of CD38-activated T cultures. Moreover, CD38 mediated cytokine induction does not require T cell proliferation or the addition of antigen presenting cells. In conclusion, human CD38 runs an activation pathway in purified T cells which operates through the induction of a cytokine profile shared by Th1 or Th2 cells.
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PMID:Secretion of IFN-gamma, IL-6, granulocyte-macrophage colony-stimulating factor and IL-10 cytokines after activation of human purified T lymphocytes upon CD38 ligation. 891 76

The cytokine regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF secretion by human umbilical cord vein endothelial cells (HUVEC) using quantitative immunoassays was studied. Unstimulated HUVEC produced no CSF. Interleukin 1 (IL-1), TNF and lipopolysaccharides (LPS) had stimulatory effects, with IL-1 being the most potent. GM-CSF and G-CSF secretion followed the same pattern, except that more GM-CSF was secreted. Exposure to stimuli for 30 min induced secretion, and detectable amounts in supernatants were found after 4 h incubation. CSF secretion was strictly regulated by the presence of a stimulus in a concentration dependent manner, and there were no signs of any endogenous downregulatory mechanism. No other cytokine tested had any stimulatory effect of its own. However, addition of IL-3 to stimulated HUVEC enhanced both GM-CSF and G-CSF secretion in a dose-dependent manner. In addition, TNF, and to a lesser degree LPS, enhanced IL-1-induced secretion. The only cytokine with a prominent downregulatory effect was IFN-gamma. IL-4 and IL-10, which downregulate CSF secretion by monocytes, had only minor effects.
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PMID:Cytokine regulation of GM-CSF and G-CSF secretion by human umbilical cord vein endothelial cells (HUVEC). 893 81

Tyrosine phosphorylation and activation of the transcription factor Stat5 occur in response to stimuli like granulocyte-macrophage colony-stimulating factor, interleukin-3, or erythropoietin that stimulate both proliferation and differentiation of hematopoietic cells. It is unclear whether Stat5 is part of a proliferative response or part of the events leading to cellular differentiation. Here we report that agents promoting differentiation but not proliferation of hematopoietic cells, like phorbol ester or both types of interferons (IFNs), activate Stat5 in promonocytic U937 cells. Both IFN types caused tyrosine phosphorylation and DNA binding of predominantly one Stat5 isoform (Stat5a) despite expression of both Stat5a and Stat5b proteins. Monocytic differentiation of U937 cells led to a strong decrease in IFN-gamma-mediated activation of Stat5 but not of Stat1. Transactivation of Stat5-target genes occurred in response to IFN-gamma, which activates both Stat5 and Stat1, but not in response to granulocyte-macrophage colony-stimulating factor, which activates only Stat5. Tyrosine phosphorylation of Stat5 is not generally part of the IFN response. IFN-gamma did not cause Stat5 activation in HeLa cells, despite the expression of both Stat5 isoforms at similar levels. By contrast, IFN-alpha caused tyrosine phosphorylation and DNA binding of exclusively the b isoform of Stat5, and activated Stat5b formed a DNA binding activity previously found in HeLa cells and designated IFN-alpha activation factor 2. Taken together, our results demonstrate that ligand binding of IFN receptors leads to an isoform-specific activation of Stat5 in a restricted number of cell lineages. Moreover, they suggest that Stat5 might be part of the differentiation response of myeloid cells.
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PMID:Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons. 894 49

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


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