Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte/macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor that stimulates a wide range of myeloid hematopoietic cells; RNAs coding for many oncogenes and cytokines including GM-CSF have a very short half-life. The motif of AUUUA is a highly conserved sequence in the 3'untranslated regions (3'UTR) of these transcripts and is repeated a number of times in these short-lived cytokines and oncogenes. These sequences play a major role in controlling stability of these transcripts. Human cancer cells were transfected with a chimeric rabbit beta-globin gene linked to either a 58 bp sequence of the AT-rich region from GM-CSF or a control sequence. We have found that irradiation stimulates accumulation of GM-CSF, interleukin-6 (IL-6), and IL-1 beta RNAs. In addition, this accumulation of GM-CSF was at least, in part, a result of increased stabilization of GM-CSF transcripts. Further experiments showed that irradiation increased levels of the chimeric beta-globin transcripts containing AUUUA sequences from GM-CSF, but not those containing the control sequences. Our results suggest that irradiation increases expression of GM-CSF RNA and that posttranscriptional stabilization requiring AUUUA sequences probably is in part one of the mechanisms producing the increased levels of GM-CSF RNA by irradiation.
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PMID:Irradiation increases levels of GM-CSF through RNA stabilization which requires an AU-rich region in cancer cells. 147 71

In addition to its hematopoietic activities, interleukin-3 (IL-3) can modulate macrophage functions. We have studied the production of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) by mouse peritoneal macrophages triggered by lipopolysaccharide (LPS) in the presence or absence of IL-3. Interleukin-3 at the concentration used (i.e., 100 U/ml) did not induce the production of any cytokines, whereas it enhanced significantly the secretion of IL-1, IL-6 and TNF by LPS-stimulated macrophages. The synergistic activity of IL-3 was observed over a wide range of Escherichia coli or Salmonella enteritidis LPS concentrations. No additive effect was noticed between IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF), another factor able to enhance LPS-induced IL-1 production. Thus, IL-3 can potentiate the inflammatory response induced by endotoxin from Gram-negative bacteria through a potentiation of cytokine production.
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PMID:Interleukin-3 enhances cytokine production by LPS-stimulated macrophages. 188 10

A number of human hematopoietic growth factors have been genetically cloned and recombinant proteins produced. Several phase I and II clinical trials have already been published and results from phase III studies are becoming available. The use of erythropoietin to alleviate chemotherapy-induced myelosuppression is being tested. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor have been extensively studied in patients receiving chemotherapy at standard or escalated doses and after bone marrow transplantation and appear to ameliorate chemotherapy-induced neutropenia and to speed bone marrow engraftment after high-dose cancer therapy. Interleukin-3 and interleukin-6 are quite early in their clinical development, but appear able to alleviate post-chemotherapy thrombocytopenia.
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PMID:Hematopoietic growth factors as supportive therapy for cancer- and chemotherapy-induced conditions. 193 23

The biologic in vivo effects of recombinant human interleukin-3 (rhIL-3) were assessed in a phase I clinical study of 30 patients with advanced malignancy. On day 1 rhIL-3 was administered by a single intravenous (IV) bolus injection, followed by subcutaneous (SC) injections once daily from day 2 to 15; at least three patients were treated at each dose level (60, 125, 250, and 500 micrograms/m2). A transient decrease of eosinophil and monocyte counts was observed immediately after IV injection of rhIL-3, whereas the neutrophil count remained unaffected. Total WBC counts and neutrophil counts increased dose dependently up to threefold, whereas a 10-fold to 50-fold rise was observed in levels of circulating eosinophils and basophils. Platelet counts increased up to twofold. Patients developed moderate increases of serum levels of soluble interleukin-2 receptors, beta 2-microglobin, and immunoglobulin M (IgM), and of the acute phase reactants, C-reactive protein (CRP), fibrinogen, and haptoglobin. An increase in interleukin-6 (IL-6) serum levels was detected in patients treated by IV bolus rhIL-3. The serum half-life of IV injected rhIL-3 was 20 +/- 3 minutes; after SC administration, 210 +/- 15 minutes. Administration of rhIL-3 was generally well tolerated, with mild fever, headache, and local reactions at the injection site being the most frequent side effects. The primary course of the underlying malignant diseases was not significantly altered by administration of rhIL-3. The results indicate that rhIL-3 acts in vivo as a multilineage hematopoietic growth factor and a weak inflammatory mediator that may be used successfully to improve states of hematopoietic failure.
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PMID:Biologic effects of recombinant human interleukin-3 in vivo. 196 May 53

The human leukemic cell line AML-193 was tested for its proliferative response to endogenously produced autocrine factors and to a variety of cytokines and colony-stimulating factors. Cells grown in the absence of GM-CSF incorporated tritiated thymidine, and this was partially reversed by adding neutralizing anti-GM-CSF antibodies to the culture medium, suggesting that it was due, at least in part, to autocrine GM-CSF production. This was confirmed by immunopurification of a GM-CSF-like activity from cell supernatant of AML-193 cells grown in serum free medium in the absence of exogenous GM-CSF. When AML-193 cells were cultured with GM-CSF in combination with other cytokines, Interleukin-1 alpha and beta (IL-1 alpha and beta), Interleukin-3 (IL-3), Interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor alpha (TNF alpha), none of them affected the concentration of GM-CSF required to induce 50% of maximum proliferation (D50). However, the maximum proliferation induced by GM-CSF alone was drastically decreased by IL-1 alpha, IL-1 beta and TNF alpha. Inhibition caused by exposure of the AML-193 to IL-1 for up to 24 hr was reversible, ruling out a direct cytotoxic effect.
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PMID:Growth regulation of the AML-193 leukemic cell line: evidence for autocrine production of granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibition of GM-CSF-dependent cell proliferation by interleukin-1 (IL-1) and tumor necrosis factor (TNF alpha). 199 54

Proliferation of acute myelogenous leukemia (AML) derived blast cells requires the presence in culture of one or more growth factors. In the majority of cases Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate clonogenicity of AML blasts, which can be synergised by Interleukin-6 (IL-6), Interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). In contrast, macrophage colony-stimulating factor (M-CSF) favors deterministic divisions. A substantial part of AML samples have clonogenic cells which, however, proliferate autonomously in vitro. The production by leukemic cells of a variety of growth or synergizing factors including GM-CSF, G-CSF, IL-1, IL-6, and Tumor Necrosis Factor (TNF) has been demonstrated and a fraction of cases will use these molecules to support clonogenic growth in an autocrine or paracrine fashion. However, unlike the situation with retrovirus-induced murine or avian leukemias, the role of production of CSFs and other cytokines by human leukemic cells in the transformational process remains uncertain.
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PMID:Control of blast cell proliferation and differentiation in acute myelogenous leukemia by soluble polypeptide growth factors. 220 37

Multinucleated cells containing tartrate-resistant acid phosphatase were produced in mouse bone marrow cultures in response to 1,25-dihydroxyvitamin D3. These cells resemble osteoclasts in their morphology, possess receptors for calcitonin, and resorb bone in culture. The effects of several hemopoietic regulatory proteins on the generation of these cells were examined in this study. Interleukin-3, granulocyte-macrophage-stimulating factor (GMCSF), and macrophage-stimulating factor strongly inhibited generation of the tartrate-resistant acid phosphatase-containing multinucleated cells with approximate EC50 values of 3, 6, and 3 colony-forming units/ml, respectively. Granulocyte colony stimulating factor, interleukin-6, and leukemia inhibitory factor had no effect on the generation of these cells. In addition, we observed that the number of these cells was reduced when the bone marrow was plated at high cell density, and that this inhibitory effect was reversed by the addition of neutralizing antibodies directed against GMCSF. These findings suggest that GMCSF and other hemopoietic factors secreted by cells in the bone marrow regulate development of the osteoclast-like cells, possibly by diverting common precursor cells to alternate pathways.
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PMID:The effect of hemopoietic growth factors on the generation of osteoclast-like cells in mouse bone marrow cultures. 240 22

We have recently shown that Abelson murine leukemia (A-MuLV) virus can transform cells in large mixed colonies to give tumorigenic myeloid cell lines capable of autonomous growth in vitro. Initial studies revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) production was consistently activated in these cells. Using a sensitive S1 RNA mapping technique and additional bioassays, we have now obtained evidence of expression of other hemopoietic growth factor genes. Uniformly 32P-labeled, single-stranded DNA probes (greater than 4 x 10(8) cpm/micrograms) were generated for interleukin 3 (IL-3) and GM-CSF using pTZ based vectors. IL-3 mRNA was detected in four of four cloned transformants (from two different infections) at approximately 1% of the level seen in pokeweed mitogen (PWM)-stimulated spleen cells. GM-CSF mRNA was detected in the two clones that showed the highest IL-3 mRNA levels. Medium conditioned by these cells was able to stimulate IL-3-dependent 32D cells, and IL-3- and GM-CSF-dependent B6SUtA cells, and also supported the growth of a variety of single and multilineage colonies in assays of mouse marrow cells even in the presence of neutralizing antibodies to GM-CSF. Rearrangements of the IL-3 and GM-CSF genes were not apparent by Southern blot analysis. Additional bioassays revealed the presence of two other growth factors: IL-6 (hybridoma growth factor or Ifn-beta 2) assayed on B13.29 cells, a factor-dependent murine B-cell hybridoma; and a new pre-B-cell stimulatory factor different from any of the above. Elucidation of the mechanism underlying this phenomenon may provide important insights into the regulation of hemopoietic growth factor gene expression and the role such genes play in human leukemogenesis.
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PMID:Activation of multiple hemopoietic growth factor genes in Abelson virus-transformed myeloid cells. 284 75

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor produced by mesenchymal and myeloid cells following activation by inflammatory stimuli. It has previously been shown that a region of the G-CSF promoter, (-200 to -165) containing the decanucleotide CK-1 element and two repeated sequences that resemble nuclear factor (NF)-interleukin-6 (IL-6) binding sites, is required for activation of the G-CSF gene by tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta. We now show that the NF-kappa B p65 protein can bind to and activate this TNF response region. There are several unusual features of this p65 interaction with the TNF response region. First, NF-kappa B p65 but not the related NF-kappa B p50 binds to the CK-1 element and a p50/65 hybrid protein that relies on the p50 rel homology domain for DNA binding does not transactivate the TNF response region. Second, p65 transactivation of this region is cell specific and requires not only its own binding site but also the NF-IL6 consensus sites. NF-IL6 also binds to the TNF response region of the G-CSF promoter. Electrophoretic mobility shift studies show that p65 and NF-IL6 can bind cooperatively to the TNF response region. The ability of this region to respond to TNF-alpha or p65 is correlated with the ability to form the p65/NF-IL6 ternary complex.
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PMID:Requirement for nuclear factor (NF)-kappa B p65 and NF-interleukin-6 binding elements in the tumor necrosis factor response region of the granulocyte colony-stimulating factor promoter. 751 99

Stem cell factor is a recently identified earliest-acting hematopoietic growth factor and a ligand for the c-kit proto-oncogen. Based on our recent observations that recombinant rat interleukin-3 (IL3), human interleukin-6 (IL6) and murine granulocyte-macrophage colony stimulating factor (GM-CSF) possessed different degrees of suppressive activities on the proliferation of LT 12 cell line derived from BNML rat leukemic model, SCF was evaluated alone and in combination with either IL3, IL6 or GM-CSF for effects on leukemopoiesis in vitro. The results indicated that SCF alone had suppressive effect on DNA synthesis and colony forming unit-leukemic blast (CFU-L) in LT12 cells. 100ng/ml of SCF caused substantial reduction in colony number and 3H-TdR uptake although this suppression was of lower magnitude than those induced by IL3, IL6 or GM-CSF. Enhanced suppression on the proliferation of LT12 cells was observed when SCF was used in combination with one of these three factors. Among these combinations, SCF+GM-CSF or SCF+IL6 resulted in more suppression on LT12 cells than SCF+IL3 did. Combination of SCF with two or three factors produced even more suppression. No apparent effect on the size of leukemic colony was seen. Furthermore, in growth kinetics study of LT12 cells in the presence of SCF production of LT12 cells declined. Thus, SCF appears to have divergent hematopoietic activities on BNML rat model: effective stimulation of granulopoiesis and weak suppression of leukemopoiesis.
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PMID:[Effects of recombinant stem cell factor on the proliferation in vitro of LT12 acute promyelocytic leukemic cell line]. 752 53


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