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)

Clinical trials to evaluate the potential of adoptive immunotherapy in cancer patients have been restricted to the use of lymphoid effector cells. Of the other probably even more important host defense system against tumor growth, the mono-nuclear phagocyte system, only monocytes (mo) have been reinfused which, however, represent immature precursor cells and acquire full functional competence only upon further maturation. This is a report on 7 patients who received autologous macrophages (MO) grown in vitro from blood mo and activated by interferon-gamma (IFN gamma). Mononuclear cells were isolated from whole blood by cytapheresis and cultured for 7 days with 2% autologous serum on hydrophobic Teflon foils. Eighteen house before cell harvest, recombinant human IFN gamma was added at 200 IU/ml. Mo-derived MO were purified by counter-current elutriation. Starting with 10(8) MO cells, therapy was escalated up to the maximal number of MO obtainable from one single preparation cycle. Currently, 26 therapies have been performed with the maximal dose being 1.7 x 10(9) MO per infusion. Except for low grade fever (less than 38 degrees C), MO autografts were well tolerated, with no side effects observed. Biological response was followed by analyzing the serum levels of beta 2-microglobulin, neopterin, interleukin-6, tumor necrosis factor, and lysozyme. While in 3 out of 7 patients serum neopterin increased in response to MO therapy, other biological response parameters remained at pretreatment levels. Radiolabeled MO were shown to first accumulate in the lungs, then to pool into liver and spleen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A new approach to adoptive immunotherapy of cancer using tumorcytotoxic macrophages grown from peripheral blood monocytes. 175 53

Cells of the mononuclear phagocyte system arise from circulating blood monocytes (MO) that undergo further maturation on leaving the vasculature and migration into the various tissues and body cavities. This terminal differentiation step is also observed in vitro when blood MO are cultured in the presence of serum. Yet, the inducing signals present in serum are not defined. We have established primary cultures from elutriation-purified blood MO and found that the active metabolite of vitamin D3 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) could induce maturation of MO to macrophages (MAC) in the absence of any serum proteins. Cells were cultured for 7 days with AB-group serum or 1,25(OH)2D3, respectively, and MO maturation analyzed by morphology, functional activity, and the expression of lineage-restricted maturation-associated antigens (MAX.1, MAX.3). At an optimal concentration of 10(-8) mol/L, 1,25(OH)2D3 promoted the development of fully differentiated MAC whose phenotype and functional competence in terms of cytokine release (tumor necrosis factor alpha, interleukin-6, fibronectin, and lysozyme) was comparable with MAC grown in serum. In conclusion, our data may add to the immunoregulatory potential of 1,25(OH)2D3, which may play an essential role in the ontogeny of the mononuclear phagocyte system.
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PMID:Induction of human monocyte to macrophage maturation in vitro by 1,25-dihydroxyvitamin D3. 226 41

Compound IX 207-887 is a novel antiarthritic agent which inhibits the release of interleukin-1 (IL-1) from human monocytes and mouse peritoneal macrophages in vitro at concentrations which are achieved therapeutically in human rheumatoid arthritis and in animal models of arthritis. In the present studies IL-1 activity in conditioned media, homogenates or lysates was monitored using four independent assay systems. Biologically active IL-1 was determined by, a) the induction of latent metalloproteinase-release from rabbit articular chondrocytes, which is relatively specific for IL-1 and b) by a sensitive thymocyte proliferation assay. Immunoreactive IL-1-beta was assayed by RIA and ELISA. In all test systems IX 207-887 significantly reduced both biologically active and immunoreactive IL-1 in culture media, whereas the levels of IL-1 in homogenates or lysates were either unaffected or only marginally reduced. The release of other monokines tested, such as interleukin-6 and tumour necrosis factor-alpha, and the secretion of lysozyme were only marginally influenced. IX 207-887 neither affected the adherence of human monocytes nor markedly inhibited IL-1 or IL-2-induced thymocyte proliferation. In the chondrocyte test no IL-1 antagonistic activity of IX 207-887 could be observed. All of these data indicate that IX 207-887 has the novel property of being an inhibitor of IL-1 release.
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PMID:Inhibition of interleukin-1 release by IX 207-887. 238 8

The terminal step in the maturation of mononuclear cells from circulating monocytes to resident macrophages is accompanied by dramatic changes in cell morphology and physiology. Applying a cultivation system which allows peripheral monocytes to undergo terminal maturation in vitro under absolutely endotoxin-free conditions, we have determined the pattern of expression of a set of eight genes by mRNA phenotyping. The results can be summarized as follows: the two protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin show a inverse pattern of expression. alpha 1-Antitrypsin mRNA is repressed, alpha 2-macroglobulin mRNA is strongly induced during maturation to macrophages. Therefore, these two genes are excellent markers of the terminal maturation. In addition, ferritin-light-chain mRNA progressively increases during the course of differentiation, providing a further marker for maturation. Gene expression as a function of activation was studied in mononuclear cells stimulated with bacterial endotoxin (lipopolysaccharide). In monocytes, complement-factor-B, interleukin-1 and interleukin-6 mRNAs are drastically induced upon lipopolysaccharide activation whereas lysozyme RNA is strongly repressed. However, the ability of all four genes to respond to endotoxin was markedly diminished or abolished in mature macrophages, indicating that susceptibility to a certain type of activation may be restricted to a specific stage of maturation. Our data show that mRNA phenotyping is excellently suited for the characterization of the differentiation and activation state of mononuclear phagocytes.
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PMID:Characterization of mononuclear-phagocyte terminal maturation by mRNA phenotyping using a set of cloned cDNA probes. 258 84

A transformed bovine peritoneal macrophage cell line was developed and characterized. Primary peritoneal macrophages were transformed by calcium-phosphate transfection with SV40 plasmid DNA. The transformed cell line retained the morphology of resident peritoneal macrophages as determined by light microscopy and histochemical analysis showed non-specific esterase activity. In addition, immunohistochemical staining of transformed peritoneal macrophages for lysozyme activity was positive. Transformed cells phagocytized Staphylococcus aureus, lysed chicken red blood cell (RBC) targets with and without opsonization and produced hydrogen peroxide radicals and interleukin-6 upon stimulation with opsonized zymosan and lipopolysaccharide, respectively. Transformed cells were also able to ingest and kill Mycobacterium paratuberculosis, an acid-fast bacillus. These results suggest that this cell line should be useful to study interactions between the bovine and intracellular pathogens.
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PMID:Immortalization and characterization of bovine peritoneal macrophages transfected with SV40 plasmid DNA. 767 7

The retroviral vector LGSN, in which the human glucocerebrosidase (GC) cDNA is driven by the Moloney murine leukemia virus (MoMLV) long terminal repeat (LTR), was tested for expression in the murine myelomonocytic leukemia cell line M1 before and after induction of differentiation with interleukin-6 (IL-6). Southern analysis of the seven transduced clones selected for neomycin resistance in Geneticin (G-418 sulfate) demonstrated one to eight copies of intact provirus with rearrangements in only two clones. Absolute levels of human GC RNA and protein increased with increased copy numbers of provirus in the clones. Upon induction with IL-6 of the seven transduced clones to the macrophage phenotype, there was no significant change, overall, in RNA levels but some increase in human GC protein levels could be detected. Although this was the average trend, considerable clonal variation in RNA and protein levels was observed upon induction. Transduction of the M1 cells did not interfere with the ability of the cells to differentiate from blasts to macrophages as seen by the appearance of membrane receptors for the constant region of immunoglobulins (Fc gamma RI) and lysozyme production in the differentiated M1 cells. Thus, the M1 cell line can be used for testing retroviral vector expression in myeloid lineages at early and late stages of differentiation. This rapid in vitro testing of potential retroviral vectors will be beneficial for gene therapy of disorders that affect differentiated macrophages such as Gaucher's disease.
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PMID:Evaluation of expression of transferred genes in differentiating myeloid cells: expression of human glucocerebrosidase in murine macrophages. 768 78

The physiologic program of macrophage differentiation normally proceeds in a coordinated manner in response to several different growth factors. Although the utilization of common receptor subunits may explain in part overlapping biologic functions, mechanisms by which unique actions are mediated remain obscure. We examined growth factor-induced macrophage differentiation in M1 leukemia cells that simultaneously display receptors for interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and Oncostatin-M (OSM). Differentiation induced by all three factors was associated with decreased expression of transcription factors myb and SCL, increased expression of macrophage markers, and suppression of proliferation. Cell lines were established in which SCL expression was enforced. In the absence of growth factors, cells were indistinguishable from parental cells. However, LIF (or OSM)-induced macrophage differentiation was perturbed; there was failure to undergo morphologic differentiation, disturbed expression of lysozyme and Mac1 alpha, and failure to suppress proliferation. Surprisingly the perturbation of macrophage differentiation did not apply to induced expression of macrophage colony-stimulating factor (M-CSF) or granulocyte colony stimulating factor (G-CSF) receptors. This dissociation of elements normally coordinated in a macrophage differentiation program applied at a clonal level. There was no disturbance of IL-6-induced macrophage differentiation. These data directly implicate SCL in components of the macrophage differentiation program (suggesting that LIF receptor/gp130 heterodimers utilize an SCL-inhibitable pathway while gp130 homodimers do not) and demonstrate differential-regulation of components of the mature macrophage phenotype.
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PMID:Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor. 781 94

Plasma lysozyme levels are elevated in several different pathological conditions. In our study we show that well differentiated human hepatoma cells Hep3B and HepG2 are active synthesis sites of lysozyme and that this synthesis can be modulated by acute phase mediators. The production and modulation of lysozyme synthesis was studied by means of Northern-blot analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a specific bioassay after treatment of the cells with interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha. Hep3B and HepG2 cells constitutively synthesize high amounts of lysozyme. Lysozyme synthesis and secretion were found to be augmented by interleukin-1 beta and tumor necrosis factor-alpha in both cell lines. Interleukin-6 caused an increase in lysozyme production in Hep3B but a decrease in the HepG2 cells. As expected, the synthesis of albumin was decreased in both cell lines. Furthermore we demonstrated that HepG2 and Hep3B cells produce a biologically active form of the enzyme as measured by a specific bioassay. The results demonstrate that lysozyme is constitutively synthesized by Hep3B and HepG2 hepatoma cell lines and that lysozyme synthesis is modulated by acute-phase mediators. Well differentiated human hepatoma cells may respond differently to different cytokines.
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PMID:Human hepatoma cells synthesize and secrete lysozyme: modulation by cytokines. 817 40

The murine myeloid leukemia cell line M1 induced by interleukin-6 (IL-6) is a model system to study the differentiation of blast cells to mature macrophages. We have recently shown that IL-6 induces the expression of the IL-4 receptor (IL-4R) in these cells. In the present study we investigate the mechanism of action of interferon-gamma (IFN-gamma), an antagonist of IL-4 in numerous cells and a cofactor in both induction and suppression of myelopoiesis, on the expression of IL-4R. Flow cytometry shows that IFN-gamma downregulates the IL-6-induced expression of IL-4R whereas it has no such effect on the high-affinity receptors for monomeric IgG2a (Fc gamma RI). As demonstrated by Scatchard analysis, the number of IL-4R decreases by more than 50% after IFN-gamma treatment whereas the receptor affinity remains unchanged. Northern analysis shows that this decrease is paralleled by a decrease in IL-4R mRNA but not Fc gamma RI or lysozyme mRNA. Nuclear run-on analysis shows that IFN-gamma suppresses the IL-6-induced transcription of the IL-4R gene, whereas actinomycin-D chase experiments showed no change of IL-4R mRNA stability. Furthermore, the production of soluble IL-4R protein is suppressed by IFN-gamma as well. These data explain how IL-4R can be modulated by IFN-gamma in myeloid cells and are consistent with the myelosuppressive capacity of IFN-gamma.
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PMID:Interferon-gamma antagonizes interleukin-6-induced expression of interleukin-4 receptors in murine myeloid cells by a transcriptional mechanism. 821 19

Murine myeloid leukemia M1 cells undergo terminal differentiation to mature macrophages after stimulation with interleukin-6 (IL-6). This process can be monitored by measuring the expression of early markers such as the high affinity receptor for monomeric IgG2a (Fc gamma RI) and Ia antigen followed by late markers such as lysozyme production and finally morphological changes from blast cells to mature macrophages. The same early markers that are expressed on M1 cells after induction with IL-6 are also expressed on monocytic cells after activation with interferon-gamma (IFN gamma). We used IL-6 and IFN gamma to investigate whether the early stages of M1 cell differentiation could be accomplished without commitment of the cells to terminal differentiation. Cytofluorometry shows that the expression of the same early differentiation markers (Fc gamma RI and Ia antigen) that are inducible by IL-6 on M1 cells can be induced by IFN gamma as well. However, stimulation with IFN gamma, in contrast to IL-6, does not induce the late differentiation markers such as lysozyme production, phagocytic activity, and morphological changes. Northern analysis supports these findings in that expression of Fc gamma RI mRNA is induced by either cytokine, whereas expression of mRNA for lysozyme is inducible by IL-6 only. Nuclear run-on analysis reveals that the changes in steady state mRNA levels of both Fc gamma RI and lysozyme are regulated by a transcriptional mechanism. These data suggest that early stages in the process of myeloid differentiation can be separately induced by IFN gamma and thus are independent from the later events induced by IL-6.
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PMID:Dissociation of early and late markers of murine myeloid differentiation by interferon-gamma and interleukin-6. 846 58


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