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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)

Colony-stimulating factor 1 (CSF-1) can act on mature macrophages to modulate their production of inflammatory cytokines. A cDNA encoding the interleukin-1 receptor antagonist (IL-1Ra) was cloned by subtractive hybridization from a CSF-1-stimulated murine macrophage cell line, sequenced, and expressed in mammalian and bacterial cells. Mouse IL-1Ra is a 22-Kd glycoprotein that is 76% identical to its human counterpart, shows considerably less similarity to IL-1 alpha and IL-1 beta, and competes with IL-1 alpha for binding to the type I IL-1 receptor normally expressed on T cells and fibroblasts. CSF-1 treatment of mouse bone marrow-derived macrophages led to a rapid and sustained increase in IL-1Ra mRNA during the G1 phase of the cell cycle as well as to increases in mRNAs encoding IL-1 alpha and IL-1 beta. Cycloheximide inhibited CSF-1-induced IL-1 alpha mRNA synthesis, but augmented IL-1 beta mRNA production and did not affect induction of IL-1Ra mRNA. No IL-1Ra mRNA was observed in CSF-1-stimulated mouse fibroblasts engineered to express CSF-1 receptors, demonstrating that its regulation depends on cell context and can be dissociated from the proliferative response. In agreement, bacterial lipopolysaccharide, a nonmitogenic activator, also induced IL-1Ra and IL-1 mRNAs in macrophages. Unlike IL-1 alpha and beta, IL-1Ra contains a signal peptide. The kinetics of its induction and its ability to gain access to the secretory compartment imply that IL-1Ra may be secreted more efficiently than IL-1, and suggest that macrophages both positively and negatively regulate the IL-1 response.
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PMID:Cloning and expression of murine interleukin-1 receptor antagonist in macrophages stimulated by colony-stimulating factor 1. 183 Apr 98

We studied the relationship between the production of the 23-Kd interleukin-1 receptor antagonist (IL-1ra) and IL-1 beta in cultures of human peripheral blood mononuclear cells (PBMC) using a specific radioimmunoassay for IL-1ra that had a sensitivity of 166 +/- 11 pg/mL. PBMC cultured without human serum made little IL-1ra or IL-1 beta. In the presence of 1% AB serum, there was no increase in IL-1 beta (0.25 +/- 0.13 ng/mL) but IL-1ra production increased sevenfold to 3.4 +/- 0.5 ng/mL. IgG (2.5 to 100 micrograms/mL IgG) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (1 to 100 ng/mL) had no significant effect on IL-1 beta production but increased IL-1ra production up to 18-fold (18.2 +/- 3.9 ng/mL). Using endotoxin as a stimulant, 82% +/- 2% of IL-1ra was secreted in comparison with 52% +/- 9% of IL-1 beta. Culture conditions of PBMC influenced the production of IL-1ra but not IL-1 beta. Rocking endotoxin-stimulated PBMC produced 75% less IL-1ra but the same amount of IL-1 beta when compared with PBMC cultured in stationary plastic tubes. Rocking IgG-or GM-CSF-stimulated PBMC also produced 75% to 80% less IL-1ra. GM-CSF or IL-1 beta at concentrations that elicited submaximal production of IL-1ra potentiated IgG-induced IL-1ra production. The production of IL-1ra and IL-1 beta are under differential regulation because serum, IgG, and GM-CSF were potent stimuli for the production of IL-1ra but not IL-1 beta, and the prevention of cell-cell contact of PBMC reduced IL-1ra but not IL-1 beta production.
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PMID:Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. 183 80

Developing megakaryocytes are distinguished from progenitor cells by the appearance of platelet proteins such as platelet factor 4 (PF 4). The human erythroleukemic cell line HEL can also be induced to produce PF 4 by incubation in phorbol esters. HEL cells were used here as a model system in which to study the phenomenon of inducible PF 4 production at both the mRNA and protein levels. The cytokines interleukin 1 beta (IL-1 beta), interleukin 3 (IL-3), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and transforming growth factor-beta (TGF-beta) were also evaluated for their effects on PF 4 mRNA induction in HEL cells.
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PMID:Platelet factor 4 mRNA expression in human erythroleukemic cells: regulation by phorbol esters and certain cytokines. 186 92

WEHI-274.3 is a cell line isolated from an in vivo-derived, murine myelomonocytic leukemia. Although the survival and growth of WEHI-274.3 cells in vitro is absolutely dependent on the addition of exogenous growth factors such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or colony-stimulating factor-1, when injected into syngeneic mice the cell line is tumorigenic. Sera from normal mice contain low levels of an activity that sustains survival of WEHI-274.3 but does not stimulate growth. In contrast, sera from mice bearing the WEHI-274.3 leukemia contained levels of CSF-1 and GM-CSF that stimulated the growth of WEHI-274.3 cells. Supernatants of cultures of WEHI-274.3 cells contained an activity that stimulated 3T3 fibroblasts to release an activity that stimulated the growth of the WEHI-274.3 cells. The 3T3-stimulatory activity released by the WEHI-274.3 cells was neutralized completely with an antiserum specific for murine IL-1 alpha, but not with antiserum specific for IL-1 beta. Moreover, WEHI-274.3 cells both in vitro and in vivo contained high levels of IL-1 alpha and IL-1 beta mRNAs. The leukemia-stimulatory activity released by the 3T3 cells was neutralized by an antiserum specific for GM-CSF. We postulate that the IL-1 alpha constitutively released by the WEHI-274.3 cells stimulates the production of GM-CSF from host cells such as fibroblasts or endothelial cells. A similar paracrine mechanism of growth stimulation may occur in acute myeloid leukemias in humans.
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PMID:The role of interleukin-1 and granulocyte-macrophage colony-stimulating factor in the paracrine stimulation of an in vivo-derived murine myeloid leukemia. 187 93

We have studied cytokine expression by the human bladder carcinoma cell line 5637 using a cDNA-PCR procedure. Transcripts for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-7, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, tumor-necrosis factor-alpha (TNF-alpha), and TNF-beta were constitutively present, whereas IL-3, IL-4, IL-5, and IL-9 mRNA sequences could not be detected. This expression pattern was not altered after 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulation (4 and 8 h) of 5637 cells. Relative expression levels of cytokines were assessed by limiting dilution of the cDNA pool. This procedure proved to be a semiquantitative technique when compared to Northern blot analysis.
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PMID:Cytokine production by the bladder carcinoma cell line 5637: rapid analysis of mRNA expression levels using a cDNA-PCR procedure. 188 17

Oligonucleotide primer pairs specific for interleukins (IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, and IL-6, as well as for granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA/cDNA were synthesized in order to detect cytokine transcripts by reverse transcription and subsequent polymerase chain reaction (RT/PCR). Analysis of RNA preparations of the human bladder carcinoma cell line 5637 by this methodology reveals expression of mRNAs for IL-1 alpha, IL-1 beta, IL-6, G-CSF, M-CSF, and for GM-CSF, whereas mRNAs for IL-2, IL-3, IL-4, and IL-5 are not detectable. These results are in agreement with data obtained by classical methods. Thus, for the cytokines IL-2, IL-3, IL-4, and IL-5, it was not possible to detect a phenomenon described as 'illegitimate transcription,' defined as the low level transcription of any gene in any cell type. This finding is of importance for the applicability of mRNA phenotyping employing RT/PCR for the determination of mRNA expression patterns. For M-CSF mRNA detection, two oligonucleotide primer pairs had to be used to distinguish between the alpha-(pcCSF17) and beta-splicing forms and to overcome the problem of non-amplification of a larger fragment in the presence of a competing smaller one, defined here as 'incomplete positivity.' For G-CSF, IL-4, IL-2, and IL-5, RT/PCR reveals two fragments. Restriction enzyme analysis of the additional fragments suggests that they may arise from alternative splicing events. For G-CSF and IL-4, exons 3 and 2 seem to be spliced out, respectively. The additional fragments for IL-2 and IL-5 RT/PCR have not yet been further characterized, but the size of the fragments makes it seem probable that exons 2 and 3 are spliced out for IL-2 and IL-5, respectively. The biological role of these alternative mRNAs has yet to be determined.
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PMID:Rapid and sensitive mRNA phenotyping for interleukins (IL-1 to IL-6) and colony-stimulating factors (G-CSF, M-CSF, and GM-CSF) by reverse transcription and subsequent polymerase chain reaction. 189 64

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

Various concentrations of 1,25-dihydroxyvitamin D3 (vit D3; 10(-9)-10(-7) M) and recombinant human tumor necrosis factor alpha (rTNF-alpha; 60-960 U/ml) were used to induce growth inhibition and differentiation of the human promyelocytic leukemia cell line HL-60 based on growth kinetics, colony formation, morphological analysis, nonspecific esterase (NSE) activity, surface antigen expression, and cytokine release. Both vit D3 (10(-8)-10(-7) M) and rTNF-alpha (60-960 U/ml) were antiproliferative against the HL-60 cells, and a cooperative effect was noted when the two inducers were used in combination. After 5 days of incubation, vit D3 induced the HL-60 cells to differentiate into monocytes/macrophages, resulting in the formation of 3.0% +/- 0.4%, 18% +/- 2.0%, and 43% +/- 3.8% of morphologically mature cells at 10(-9), 10(-8), and 10(-7) M, respectively. The induced cells were NSE positive and expressed monocyte-associated antigens (EBM11, CD11b, and HLA-DR). Conversely, rTNF-alpha (60-960 U/ml) was unable to trigger the HL-60 cells to differentiate. However, rTNF-alpha could apparently increase the proportion of the morphologically mature and NSE-/antigen-positive cells when used in combination with vit D3 (10(-9)-10(-8) M). Following differentiation induction, HL-60 cells from vit D3-treated HL-60 cultures acquired the ability to secrete certain monokines, including interleukin 1 beta (IL-1 beta), prostaglandin E2 (PGE2), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and adding rTNF-alpha in addition to vit D3 invariably increased the production of IL-1 beta and PGE2.
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PMID:Growth inhibition and differentiation in HL-60 leukemia cells induced by 1,25-dihydroxyvitamin D3 and tumor necrosis factor alpha. 191 3

Philadelphia chromosome1 positive (Ph1) chronic myelogenous leukemia (CML) is characterized by metamorphosis of the chronic phase to blastic crisis. However, cellular events associated with this transition are poorly understood. To examine the possible participation of hematopoietic growth factors in this process, we studied growth factor expression in adherent layers of bone marrows derived from CML Ph1 patients in various stages of the disease. Interleukin-1 beta (IL-1 beta) and IL-6 mRNA were expressed in five of six patients, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in one of six patients with myeloid/undifferentiated blast crisis. In addition, leukemia inhibitory factor (LIF) expression was increased in four of six patients with myeloid/undifferentiated blast crisis phase of the disease. IL-1 beta was also detected in bone marrow adherent layer conditioned medium from two of these patients. These results were in sharp contrast to the lack of detectable levels of uninduced IL-1 beta, IL-6, and GM-CSF mRNA, in samples derived from 4 patients in lymphoid blastic crisis, 3 in accelerated, and 11 in chronic phases of the disease, or from normal controls. The possibility of a paracrine loop formation, whereby the adherent layers representing the bone marrow stroma are induced to express hematopoietic growth factors, was supported by our finding IL-1 beta mRNA expression in the leukemic blast cells in three of four studied patients in blast crisis and IL-1 beta protein production in seven of eight patients studied. Finally, coculturing CML blast crisis cells onto pre-established adherent layers induced the expression of both IL-1 beta and IL-6 genes. From this preliminary study, it appears that abnormal expression of growth factors is a common event with CML Ph1 progression. We hypothesize that IL-1 beta generated by the transformed malignant clone stimulates the marrow stroma to produce various growth factors, and that this process may play a role in disease progression.
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PMID:Alteration in bone marrow adherent layer growth factor expression: a novel mechanism of chronic myelogenous leukemia progression. 193 51

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.
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PMID:Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. 194 Jul 99


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