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)

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
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PMID:Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice. 1636 58

Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DeltaKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DeltaKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x(L) expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.
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PMID:Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells. 1651 18

Colony-stimulating factor-1 (CSF-1) induces osteoclast spreading that requires activation of c-Src and phosphatidyl inositol 3-kinase (PI3-K), both of which are recruited to activated c-Fms, the CSF-1 receptor. The present report provides evidence that the hemopoietic guanine nucleotide exchange factor (GEF), Vav, and its target GTPase, Rac, lie downstream from this initial signaling complex. CSF-1 treatment of osteoclast-like cells induced translocation of Vav to the plasma membrane, an increase in its phosphotyrosine content, and a concomitant decline in the amount of phosphoinositol 4,5-bisphosphate bound to Vav, changes known to induce Vav's GEF activity. CSF-1 induced the association of Vav and Rac and increased Rac's GTPase activity. CSF-1 also induced rapid translocation of Rac to the periphery of spreading neonatal rat osteoclasts where it co-localized primarily with Vav3 and to a lesser extent with Vav1. Wortmannin, an inhibitor of PI3-K, blocked CSF-1-induced Rac translocation and prevented CSF-1-induced spreading and actin reorganization in osteoclasts. CSF-1-induced osteoclast spreading was not significantly reduced in osteoclasts isolated from Vav1 knock-out mice and Vav1 knock-out mice had normal bone density. Microinjection of constitutively active Rac, but not constitutively active Cdc42 or RhoA, induced lamellipodia formation and osteoclast spreading, mimicking the effects of CSF-1. Dominant-negative Rac blocked CSF-1-induced osteoclast spreading, whereas neither dominant-negative Cdc42 nor C3, an inhibitor of RhoA, affected the response to CSF-1. These data demonstrate that Vav and Rac lie downstream from activated PI3-K in CSF-1-treated osteoclasts and that Rac is required for CSF-1-induced cytoskeletal remodeling in these cells.
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PMID:Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. 1695 Jun 70

Activated T lymphocytes either stimulate or inhibit osteoclastogenesis from haematopoietic progenitors in different experimental models. To address this controversy, we used several modes of T lymphocyte activation in osteoclast differentiation--mitogen-pulse, anti-CD3/CD28 stimulation and in vivo and in vitro alloactivation. Osteoclast-like cells were generated from non-adherent immature haematopoietic monocyte/macrophage progenitors in murine bone-marrow in the presence of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) and monocyte-macrophage colony-stimulating factor (M-CSF). All modes of in vivo and in vitro T lymphocyte activation and both CD4(+) and CD8(+) subpopulations produced similar inhibitory effects on osteoclastogenesis paralleled by enhanced dendritic cell (DC) differentiation. Osteoclast-inhibitory effect was associated with T lymphocyte activation and not proliferation, and could be replaced by their culture supernatants. The stage of osteoclast differentiation was crucial for the inhibitory action of activated T lymphocytes on osteoclastogenesis, because the suppressive effect was visible only on early osteoclast progenitors but not on committed osteoclasts. Inhibition was associated specifically with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by the mechanism of progenitor commitment toward lineages other than osteoclast because activated T lymphocytes down-regulated RANK, CD115, c-Fos and calcitonin receptor expression, and increased differentiation towards CD11c-positive DC. An activated T lymphocyte inhibitory role in osteoclastogenesis, confirmed in vitro and in vivo, mediated through GM-CSF release, may be used to counteract activated bone resorption mediated by T lymphocyte-derived cytokines in inflammatory and immune disorders. We also demonstrated the importance of alloactivation in osteoclast differentiation and the ability of cyclosporin A to abrogate T lymphocyte inhibition of osteoclastogenesis, thereby confirming the functional link between alloreaction and bone metabolism.
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PMID:Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down-regulation of receptor activator of nuclear factor-kappaB and c-Fos. 1696 9

We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.
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PMID:Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a poor prognosis. 1720 58

It is well known that many burn patients experience psychopathological disorders prior to burn injury. However, it is not known whether individuals that have been exposed to chronic psychological stresses will respond differently than unstressed individuals when challenged by a burn injury. In this study, we assessed whether chronic psychogenic stress prior to burn injury had any significant impact on burn injury-induced alterations in the myeloid compartment in the bone marrow and serum cytokine levels utilizing a well-controlled purely psychogenic stress model (predator exposure). Mice were individually caged and exposed to a Long Evans rat for 1 hr a day on 3 consecutive days prior to a 15% total body surface area flame burn. Four days after burn injury, bone marrow and serum were collected to assess myeloid cells and cytokine levels, respectively. Bone marrow cells were cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF) to assess clonogenic ability. Flow cytometry was also used to characterize the populations of myeloid cells based on Gr-1 and CD11b staining intensity and to determine the expression of the macrophage colony-stimulating factor receptor (M-CSFR). Serum was assayed for IL-6, IL-12p70, MCP-1, and IFN-gamma by multiplexed sandwich enzyme-linked immunoabsorbent assay (ELISA). We found that predator exposure prior to burn injury ablated the burn-induced increase in myeloid colony formation and attenuated the burn-induced increases in immature monocytes and immature neutrophils in the bone marrow, as well as MCP-1 levels in the serum. Conversely, psychogenic stress exaggerated the burn-induced increase in the number of M-CSFR-positive cells. This study is the first to show the effects of a pure psychogenic stressor (predator exposure) on burn-induced alterations of the immune system. The clinical ramifications of our findings remain to be elucidated.
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PMID:Psychogenic stress prior to burn injury has differential effects on bone marrow and cytokine responses. 1725 33

We diagnosed an 86-year-old woman with chronic neutrophilic leukemia (CNL) because she showed sustained leukocytosis dominated by mature neutrophils, hepatosplenomegaly, high neutrophilic alkaline phosphatase score, absence of the Ph chromosome, low serum level of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and no evidence of leukemoid reaction. We found that the extent of stimulation of her neutrophil functions by G-CSF and GM-CSF was greatly reduced compared to healthy donars neutrophils. We showed that CNL neutrophils have intact expression of granulocyte colony-stimulating factor receptor (G-CSFR) and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR). This suggests that failure of enhancement by G-CSF and GM-CSF in CNL neutrophil functions might be due to disturbances in the intracellular domains of G-CSFR and GM-CSFR, regardless of external cytokine stimulation. However, the patient's neutrophils did not show any mutations in the G-CSFR and GM-CSFR intracellular critical regions. We also showed that stat3 and mitogen-activated protein kinase activation by G-CSF or GM-CSF in the patient's neutrophils were significantly lower than those in healthy donor neutrophils. These results suggest that deficiency of CNL neutrophil function might be due to insufficiency of some inflammatory cytokine-specific signaling. Hence, we are the first to show that CNL neutrophils have partially insufficiency in some cytokine-specific signaling. Further studies are needed to elucidate the signal transduction pathways relating to functional defects in CNL neutrophils.
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PMID:Neutrophil function and cytokine-specific signaling in chronic neutrophilic leukemia. 1824 Dec 14

HIV-1 infection impairs alveolar macrophage immune function and renders patients susceptible to pneumonia by poorly understood mechanisms. Alveolar macrophage maturation and function depends on granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced and secreted by the alveolar epithelium. Macrophages respond to GM-CSF through the GM-CSF receptor (GM-CSFR), which has a binding subunit (GM-CSFRalpha) and a signaling subunit (GM-CSFRbeta). In this study, we measured GM-CSFR expression and alveolar macrophage function in a transgene HIV-1 rat model (NL4-3Delta gag/pol); this construct bears a pro-virus with gag and pol deleted, but other HIV-1-related proteins, such as gp120 and Tat, are expressed, and the rats develop an AIDS-like phenotype as they age. We first determined that HIV-1-transgenic expression selectively decreased alveolar macrophage expression of GM-CSFRbeta and impaired bacterial phagocytosis in vitro. Next, we examined the role of zinc (Zn) deficiency as a potential mechanism underlying these effects, and determined that HIV-1-transgenic rats have significantly lower levels of Zn in the alveolar space and macrophages. To test the direct effect of Zn deficiency on macrophage dysfunction, we treated rat alveolar macrophage cell line with a Zn chelator, N,N,N',N'-tetrakis-(2-pyridyl-methyl) ethylenediamine, and this decreased GM-CSFRbeta expression and phagocytosis. In parallel, treatment with Zn acetate in vitro for 48 hours restored intracellular Zn levels and phagocytic function in alveolar macrophages from HIV-1-transgenic rats. Taken together, these data suggest that pulmonary Zn deficiency could be one of the mechanisms by which chronic HIV-1 infection impairs alveolar macrophage immune function and renders these individuals susceptible to serious lung infections.
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PMID:HIV-1-transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis. 1831 38

T helper (Th) 2-type cytokines play a dominant role in allergic inflammation. Accumulating evidence suggests that Th1-type cytokines antagonize Th2-type cytokine responses; however, recent studies demonstrate that Th1 cytokines might enhance Th2 immune responses. We examined whether interferon (IFN)-gamma, a representative Th1 cytokine, modifies the effector functions of human eosinophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5. GM-CSF and IL-5 have significant functional homology, and contribute to the regulation of Th2 immunity. After the pretreatment of eosinophils with IFN-gamma, GM-CSF- or IL-5-induced eosinophil functions were examined, including superoxide anion generation, degranulation, adhesion, expression of GM-CSF receptor (R), IL-5R, or CD11b, and phosphorylation of intracellular signaling molecules. Superoxide anion generation was measured using the cytochrome c reduction method. Degranulation and cell adhesion were evaluated based on eosinophil-derived neurotoxin (EDN) contents in supernatants or adherent cells. Phosphorylation of signaling molecules was analyzed using a multiplex beads array system. Preincubation with IFN-gamma resulted in enhanced GM-CSF- or IL-5-induced superoxide anion generation and degranulation of human eosinophils, whereas stimulus-induced eosinophil adhesion was unaffected. In addition, IFN-gamma did not influence the expression of GM-CSFR, IL-5R, and CD11b. Furthermore, IFN-gamma upregulated GM-CSF- or IL-5-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and activating transcription factor (ATF)-2. Finally, we confirmed that MAPK inhibitors blocked the enhancement of stimuli-induced superoxide anion generation of IFN-gamma treated eosinophils. In conclusion, IFN-gamma might upregulate ERK, p38, or JNK/ATF-2 phosphorylation induced by GM-CSF or IL-5, leading to enhanced cytokine-induced eosinophil superoxide generation and degranulation.
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PMID:Interferon-gamma enhances human eosinophil effector functions induced by granulocyte-macrophage colony-stimulating factor or interleukin-5. 1844 Jun 51

Immunotherapy is now considered in acute myelogenous leukemia (AML). A dendritic cell (DC) phenotype can be induced in primary human AML cells by in vitro culture in the presence of various cytokine combinations. The aim was to investigate whether this phenotypic alteration is associated with altered chemokine release. AML cells were cultured according to four protocols that have been characterized in detail for AML-DC induction: (1) granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) days 1-14 and tumor necrosis factor-alpha (TNF-alpha) for days 6-14, (2) GM-CSF + IL-4 + TNF-alpha + FMS-like tyrosine kinase 3-ligand (Fl3-L) for 8 days, (3) GM-CSF + IL-4 + TNF-alpha + Flt3-L + stem cell factor (SCF) + transforming growth factor-beta1 (TGF-beta1) for 8 days, and (4) 25 Gy gamma-irradiation combined with culture in the presence of GM-CSF + SCF + IL-3 for 4 days. Significantly increased AML-DC release of CCL17 and CCL22 was observed for protocols 1, 2, and 3, whereas effects on CCL2-5, CXCL8, and CXCL10 differed in all protocols. Neutralization studies using a transwell migration assay demonstrated the increased level of CCL17 and CCL22 release was important for AML-DC chemotaxis of normal T cells. Induction of a dendritic AML cell phenotype is associated with an altered chemokine release profile. Detailed characterization of chemokine release should be included in future studies of AML-DC vaccination.
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PMID:In vitro induction of a dendritic cell phenotype in primary human acute myelogenous leukemia (AML) blasts alters the chemokine release profile and increases the levels of T cell chemotactic CCL17 and CCL22. 1854 60


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