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)

Interleukin-12 (IL-12) is a monocyte/macrophage-derived cytokine that is critical for T lymphocyte and natural killer cell activities and functions. In this study, we examined the regulation of IL-12 expression by human monocytes in response to bacterial lipopolysaccharide (LPS). Several novel aspects of IL-12 induction from monocytes were shown. Optimal expression of IL-12 mRNA and bioactivity required specific priming of monocytes by interferon-gamma (IFN-gamma) before LPS stimulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) provided an equivalent priming stimulus for LPS-induced tumor necrosis factor (TNF) and IL-12 p40 mRNA, but primed poorly for LPS-inducible p35 message and secreted IL-12 activity. Macrophage colony-stimulating factor (M-CSF), although a potent survival factor for monocytes, showed no priming activity for IL-12 production. Time course experiments demonstrated independent regulation of p40 and p35 by IFN-gamma and LPS. LPS inducibility of p40 expression required only a brief exposure to IFN-gamma (2 hours), while prolonged exposure (+/- 24 hours) to IFN-gamma resulted in diminishing levels of p40 mRNA. p35 inducibility (by LPS) required a longer exposure to IFN-gamma (8 to 16 hours), and continued to be inducible up to 40 hours following IFN-gamma priming. Both mRNAs were rapidly induced (1 to 2 hours) in IFN-gamma-primed monocytes; p35 message reached a plateau by 2 hours, while p40 continued to accumulate. Finally, both p40 and p35 were directly induced by LPS in the presence of cycloheximide. These results indicated that both p40 and p35 are LPS-inducible in monocytes following IFN-gamma pretreatment, and that the regulated expression of p35 controls the level of active IL-12 protein in purified human monocytes. The selectivity of priming by IFN-gamma is in accord with a putative role for IL-12 in the initiation and amplification of TH1-type responses.
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PMID:Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes. 760 94

In this study, we investigated the effect of recombinant human interleukin-6 (IL-6) on colony-forming cells for granulocytes and macrophages (CFU-GM) cultured in suspension. IL-6 when used alone did not induce proliferation of highly purified CD34+ human hematopoietic progenitors. Moreover, no influence of IL-6 was observed on the proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte (G)-CSF. However, a marked survival enhancement (GM-CSF 228 +/- 42%, p < 0.01, and G-CSF 137 +/- 9%, p < 0.05) was observed when CD34+ cells were preincubated with IL-6 for 6 days. This survival effect became even more pronounced under serum-poor conditions (GM-CSF 380 +/- 80%, p < 0.01, and G-CSF 180 +/- 20%, p < 0.01) and could also be demonstrated at the single cell level in a colony-forming assay. By analysis of subpopulations of CD34+ bone marrow (BM) cells selected on the basis of CD45RO expression, the observed IL-6-mediated survival effect was found to be restricted to the CFU-GM containing CD45RO- subset. Our data show that IL-6 is a survival factor for CFU-GM.
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PMID:Interleukin-6 is a survival factor for committed myeloid progenitor cells. 769 39

Because leukemia inhibitory factor (LIF) has little or no effect on murine hematopoietic progenitor cell growth yet enhances hematopoiesis in vivo, we sought to determine whether the effects of LIF were directly or indirectly mediated, or a combination of both. Although LIF alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) has no effect on colony formation of unfractionated bone marrow cells (BMCs), it enhances M-CSF-induced colony formation. In comparison, LIF synergizes with IL-3, GM-CSF, M-CSF, and Steel Factor (SLF) to promote the colony formation of partially purified lineage-negative (Lin-) BM progenitors without altering their differentiation. These effects were directly mediated since identical results were observed in single-cell assays. Comparing the effect of LIF with other members of this subclass of hematopoietins (IL-6, oncostatin M [OSM], and ciliary neurotrophic factor [CNTF]), we found that while LIF and IL-6 equally synergize with M-CSF and SLF to promote the colony formation of Lin- BMCs, OSM, and CNTF have no effect. In agreement with OSMs ability to directly bind gp130, preincubation of BMCs with OSM inhibits progenitor cell growth stimulated by the combination of LIF or IL-6 plus SLF. LIF can also directly enhance the growth of further purified more primitive Lin- c-kit+ progenitor cells in the presence of IL-3, GM-CSF, or SLF. Thus, LIF can directly synergize with growth factors to promote the proliferation of purified hematopoietic progenitors, suggesting that the direct effects of LIF on hematopoietic cell growth can, in part, explain the observed hematopoietic effects in vivo. This is a US government work. There are no restrictions on its use.
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PMID:Direct synergistic effects of leukemia inhibitory factor on hematopoietic progenitor cell growth: comparison with other hematopoietins that use the gp130 receptor subunit. 870 42

Hematopoiesis is a complex process of regulated cellular proliferation and differentiation from the primitive stem cells to the final fully differentiated cell. The long and extensive search for a factor specifically regulating megakaryocytopoiesis led to the cloning of a hormone, here called thrombopoietin (TPO), that specifically promotes proliferation and differentiation of the megakaryocytic lineage. The availability of recombinant TPO and its imminent clinical use has made a more detailed understanding of its effects on hematopoietic cells more urgent. Normal megakaryocyto- and thrombopoiesis occurs predominantly in the bone marrow, a difficult organ to study in situ, particularly in humans, due to the low numbers of megakaryocytic progenitors and the consequent difficult isolation as pure populations. Thus, we developed an in vitro system which may allow us to address questions regarding the biology of TPO. The acute myeloid leukemia (AML)-derived cell lines HU-3, M-07e, M-MOK and TF-1 have absolute dependence on granulocyte-macrophage colony-stimulating factor (GM-CSF). We cultured these cells long term (> 6 months) in the continuous presence of TPO (omitting GM-CSF). TPO alone supported the maintenance and expansion of these sister cell lines, HU-3/TPO, M-07e/TPO, M-MOK/TPO and TF-1/TPO, that displayed somewhat longer doubling times, a larger cell size, and a higher percentage of polynucleated giant cells and slightly adherent cells than the corresponding countercultures grown with GM-CSF. In the absence of TPO the cells died quickly, within a few days; thus, the TPO-grown cell lines have an absolute dependence on this factor, but could all be switched back to growth with GM-CSF. In comparison with the GM-CSF-treated cells, the receptors for GM-CSF and interleukin-3 (IL-3) were down-regulated and the receptors for stem cell factor (SCF) and TPO were up-regulated in the TPO-exposed cells. A short-term proliferation assay showed a stronger response of the TPO-cell lines to erythropoietin, GM-CSF, IL-3, PIXY-321, SCF and TPO than the GM-CSF-cell lines. Flow cytometric analysis of the GM-CSF-and TPO-cultured lines displayed an up-regulation of the megakaryocytic surface markers CD41, CD42 and CD61, and a down-regulation of the erythroid marker glycophorin A in the latter cell lines, suggesting some differentiation along the megakaryocytic lineage. Thus, in long-term exposure, TPO appears to have both a proliferative and a differentiative effect on responsive cells. Under serum-deprived culture conditions, TPO acted as a survival factor on the TPO-cell lines. Taken together, these findings indicate that the TPO-dependent cell lines represent important biological reagents for further characterization of the biology of TPO and should also provide a great aid for future in vitro experiments aimed at elucidating megakaryocyto- and thrombopoiesis.
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PMID:Thrombopoietin supports the continuous growth of cytokine-dependent human leukemia cell lines. 909 95

mcl-1, a bcl-2 family member, was originally identified as an early gene induced during differentiation of ML-1 myeloid leukemia cells. In the present study, we demonstrate that Mcl-1 is tightly regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway. Upon deprivation of survival factor from TF-1 myeloid progenitor cells, Mcl-1 levels quickly dropped prior to visible detection of apoptosis of these cells. Upon restimulation of these deprived cells with GM-CSF, the mcl-1 mRNA was immediately induced and its protein product was accordingly resynthesized. Analysis with Ba/F3 cells expressing various truncation mutants of the GM-CSF receptor revealed that the membrane distal region between amino acids 573 and 755 of the receptor beta chain was required for mcl-1 induction. Transient-transfection assays with luciferase reporter genes driven by various regions of the mcl-1 promoter demonstrated that the upstream sequence between -197 and -69 is responsible for cytokine activation of the mcl-1 gene. Overexpression of mcl-1 delayed but did not completely prevent apoptosis of cells triggered by cytokine withdrawal. Its down regulation by antisense constructs overcame, at least partially, the survival activity of GM-CSF and induced the apoptosis of TF-1 cells. Taken together, these results suggest that mcl-1 is an immediate-early gene activated by the cytokine receptor signaling pathway and is one component of the GM-CSF viability response.
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PMID:mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. 967 97

Ciliary neurotrophic factor (CNTF), like tumor necrosis factor-alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), is a cytokine with neurotrophic properties. Since all three cytokines are found in the periphery as well as brain, and since TNF and GM-CSF cross the blood-brain barrier (BBB) by a saturable mechanism, we investigated whether CNTF also saturably enters the brain from the blood. We found that CNTF crosses the BBB rapidly, with a rate of entry (Ki) of 4.60 (+/-0.78) x 10(-4) ml/g min, considerably faster than that of the 99mTc-albumin control. The Ki was reduced more than 3-fold by addition of excess unlabeled CNTF. The results indicate that CNTF is saturably transported across the BBB from blood to brain.
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PMID:Saturable entry of ciliary neurotrophic factor into brain. 1021 13

CD137 (ILA/4-1BB), a member of the tumor necrosis factor (TNF) receptor family, promotes adherence and prolongs survival of human peripheral monocytes. It induces a strong expression of macrophage colony-stimulating factor (M-CSF), an essential monocyte survival factor. Monocyte survival induced by CD137 is primarily mediated by M-CSF and to a lesser extent by granulocyte-macrophage colony-stimulating factor and IL-3. Survival and induction of M-CSF are mediated via reverse signaling through a CD137 ligand expressed constitutively by peripheral monocytes.
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PMID:Identification of CD137 as a potent monocyte survival factor. 1038 Sep 6

Hematopoietic progenitor cells from Fanconi anemia (FA) group C (FA-C) patients display hypersensitivity to the apoptotic effects of gamma interferon (IFN-gamma) and constitutively express a variety of IFN-dependent genes. Paradoxically, however, STAT1 activation is suppressed in IFN-stimulated FA cells, an abnormality corrected by transduction of normal FANCC cDNA. We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1. Expression and phosphorylation of IFN-gamma receptor alpha chain (IFN-gammaRalpha) and JAK1 and JAK2 tyrosine kinases were equivalent in both normal and FA-C cells. However, in coimmunoprecipitation experiments STAT1 did not dock at the IFN-gammaR of FA-C cells, an abnormality corrected by transduction of the FANCC gene. In addition, glutathione S-transferase fusion genes encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bound to STAT1 in lysates of IFN-gamma-stimulated B cells and IFN-, granulocyte-macrophage colony-stimulating factor- and stem cell factor-stimulated MO7e cells. Kinetic studies revealed that the initial binding of FANCC was to nonphosphorylated STAT1 but that subsequently the complex moved to the receptor docking site, at which point STAT1 became phosphorylated. The STAT1 phosphorylation defect in FA-C cells was functionally significant in that IFN induction of IFN response factor 1 was suppressed and STAT1-DNA complexes were not detected in nuclear extracts of FA-C cells. We also determined that the IFN-gamma hypersensitivity of FA-C hematopoietic progenitor cells does not derive from STAT1 activation defects because granulocyte-macrophage CFU and erythroid burst-forming units from STAT1(-/-) mice were resistant to IFN-gamma. However, BFU-E responses to SCF and erythropoietin were suppressed in STAT(-/-) mice. Consequently, because the FANCC protein is involved in the activation of STAT1 through receptors for at least three hematopoietic growth and survival factor molecules, we reason that FA-C hematopoietic cells are excessively apoptotic because of an imbalance between survival cues (owing to a failure of STAT1 activation in FA-C cells) and apoptotic and mitogenic inhibitory cues (constitutively activated in FA-C cells in a STAT1-independent fashion).
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PMID:The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. 1084 98

Allergic asthma is characterized by pulmonary infiltration and accumulation of eosinophils, which is enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF). T cells, fibroblasts, and eosinophils themselves produce GM-CSF, suggesting it functions in the lung microenvironment as a survival factor. However, the amounts and the mechanism by which GM-CSF supports eosinophil survival remain poorly understood. We have previously reported that human peripheral blood eosinophils (PBEo) can be transfected with GM-CSF mRNA using particle-mediated gene transfer (PMGT). Using this technology, GM-CSF mRNA was introduced into resting PBEo, and GM-CSF production and cell survival were assessed. GM-CSF protein was undetectable (< 1 pg/ml) in the supernatant but present intracellularly at very low levels. Unexpectedly, the in vitro survival of transfected PBEo was 4-fold greater than that of controls. Neutralizing anti-GM-CSF but not anti-interleukin-5 (anti-IL-5) antibody added up to 24 h after transfection abolished enhanced survival, demonstrating that the continuous presence of GM-CSF was required. Conditioned medium prepared from transfected PBEo prolonged the survival of naive cells. Comparable survival activity was mimicked by a single dose of 100-500 pg/ml or multiple administrations of 0.1 pg/ml recombinant human GM-CSF (rHuGM-CSF). Survival was completely inhibited by a Jak2 inhibitor, suggesting that GM-CSF-mediated survival involved signaling through the Jak-Stat pathway. Thus, autocrine production of low levels of GM-CSF by a minority of PBEo can block apoptosis of the entire culture by a minute but sustained GM-CSF release.
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PMID:Minute quantities of granulocyte-macrophage colony-stimulating factor prolong eosinophil survival. 1124 76

Mast cells and macrophages have an important role in immunity and inflammation. Because mice are used extensively for experimental studies investigating immunological and inflammatory responses, we examined mast cell and macrophage distribution in normal murine tissues. Mast cells were abundant in the murine dermis, tongue, and skeletal muscle but were rarely found in the heart, lung, spleen, kidney, liver, and the bowel mucosa. In contrast, dogs exhibited large numbers of mast cells in the lung parenchyma, liver, and bowel. Some murine dermal mast cells had long cytoplasmic projections filled with granular content. Mouse mast cells demonstrated intense histamine immunoreactivity and were identified with histochemical enzymatic techniques for tryptase and chymase. Macrophages, identified using the monoclonal antibody F4/80, were abundant in the spleen, lung, liver, kidney, and bowel but relatively rare in the heart, tongue, and dermis. Using a nuclease protection assay we investigated mRNA expression of stem cell factor (SCF), a crucial survival factor for mast cells, and the macrophage growth factors macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF). Stem cell factor mRNA was highly expressed in the murine lung. Relatively low levels of SCF mRNA expression were found in the tongue and earlobe, which are tissues containing a high number of mast cells. Macrophage CSF and GM-CSF mRNA was highly expressed in the lung and spleen. The murine heart, an organ with a low macrophage content, expressed high levels of M-CSF but negligible levels of GM-CSF mRNA. Constitutive growth factor mRNA expression in murine tissues without significant populations of mast cells and macrophages may suggest an alternative role for these factors in tissue homeostasis.
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PMID:Mast cells and macrophages in normal C57/BL/6 mice. 1212 46


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