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)

Stromal cell lines derived from canine long-term bone marrow cultures (LTBMC) were characterized regarding the expression of growth factors and especially the localization of stem cell factor (SCF) (c-kit ligand). One cell line (DO64) was immortalized by transformation with a retroviral vector containing the open reading frames (ORFs) E6 and E7 of the human papilloma virus type 16 (HPV-16). Transfection did not change cellular characteristics but rendered the cell line more independent from culture conditions. The transformed line DO64 consisted mainly of fibroblast-like cells. In addition, some cells showed endothelial and some smooth-muscle cell features. Stromal cells expressed a broad spectrum of surface markers, including low levels of major histocompatibility-complex (MHC) class-II antigens. A new murine monoclonal antibody (MAb), RG7.6 (IgG1), specific for canine SCF, recognized the majority of fibroblast-like stromal cells. The staining pattern for SCF showed perinuclear and intracytoplasmic dense areas. Immunoelectron microscopy revealed the localization of SCF in secretory vesicles, the perivesicular cytoplasm, and bound to the cytoplasmatic membrane. RNA analysis showed that stromal cells transcribed, in addition to SCF, messages for granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte CSF (GM-CSF), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-beta). In summary, we have established and characterized canine marrow-derived stromal cell lines, and using the new MAb RG7.6, we have localized SCF to cytoplasmatic vesicles as well as the membrane of stromal cells.
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PMID:Ultrastructural localization of stem cell factor in canine marrow-derived stromal cells. 752 83

We examined the measurement and the diagnostic value of cerebrospinal fluid interleukin-6 (CSF IL-6) in meningitis. The cytokine was measured by bioassay (B9 hybridoma cell line) and by immunoassay (in-house radioimmunoassay). We compared the diagnostic value of CSF IL-6 determination with that of other biochemical markers of meningitis. Although there was significant correlation between bioactive and immunoactive IL-6 (r = 0.724, P < 0.001), results were frequently different with biological/immunological ratios ranging from 0.2 to 24.3 (mean 4.6). Gel permeation chromatography suggested that the discrepancy in biological and immunological activities was not due to molecular heterogeneity, but may be explained by the presence of a synergistic factor. Interleukin-6 concentration was markedly elevated in CSF from most patients with bacterial meningitis compared to patients with viral meningitis and those without evidence of infection. However, low IL-6 levels by radioimmunoassay did not exclude bacterial meningitis (sensitivity 86%). CSF total protein and CSF glucose were significantly different between all three groups, but there was no significant difference in lactate concentration between virally infected and normal CSF, both of which had lower lactate concentrations than those in bacterial infection. CSF IL-6 measurement had greater sensitivity, specificity and predictive value than these other biochemical markers, and hence a rapid assay for IL-6 in CSF may contribute to the early diagnosis of bacterial infection.
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PMID:Cerebrospinal fluid interleukin-6 and its diagnostic value in the investigation of meningitis. 763 33

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen-4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor-alpha, transforming growth factor-beta 1, or transforming growth factor-beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.
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PMID:Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. 763 39

The aim of the present study was to evaluate whether the erythropoietic response to hemolysis can be mediated by other regulatory peptides in addition to erythropoietin. For this purpose, we have investigated the influence of erythrophagocytosis by human monocytes and macrophages on the mRNA expression of several growth factor genes, including interleukin-3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF) and erythroid potentiating activity (EPA), which are supposed to influence erythropoiesis. Immunologically mediated erythrophagocytosis increased the expression of EPA mRNA (2 to 3 times). Such increase appeared to be specifically associated with phagocytosis of erythrocytes, since phagocytosis of yeast microorganisms or antibody-coated latex particles had no effect on EPA gene expression. Yeast, however, powerfully stimulated the expression of GM-CSF, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) mRNAs which, with the exception of G-CSF, were not influenced by erythrophagocytosis. Erythropoietin and IL-3 mRNAs were never detected in cultured monocytes, either in control or in treated samples. Our findings may suggest that phagocytosis of erythrocytes by monocytes/macrophages increases the expression, and possibly the production, of EPA. This could in turn potentiate the erythropoietic response to extravascular hemolysis by increasing the number of cells responsive to erythropoietin. Thus, EPA might be a mediator of an end-product positive feedback on the rate of red cell production.
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PMID:Erythrophagocytosis increases the expression of erythroid potentiating activity mRNA in human monocyte-macrophages. 767 89

Monocytes and macrophages show marked phenotypic variation dependent on their tissue of origin. Peripheral blood monocytes have been found to be sources of a variety of cytokines, but isolated marrow macrophages have not been characterized in this regard. Marrow macrophages form a predominant component of murine adherent Dexter stromal cells and can be isolated by sequential explant culture in colony-stimulating factor-1 (CSF-1). We have studied murine (Balb/c) bone marrow macrophage (BMM) cytokine production in the presence or absence of CSF-1, the lectin pokeweed mitogen (PWM) or interleukin-3 (IL-3). Biologic activity in conditioned media (cm) from control and induced BMM was assessed using the factor-dependent cell lines 32D, NFS-60, T1165, MC-6 and FDC-P1. Cell line stimulation and antibody blocking indicated the presence of c-kit ligand, interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). This stimulatory activity was increased by exposure to PWM or the combination of CSF-1 and PWM or CSF-1 and IL-3. CSF-1, as determined by radioimmunoassay (RIA), was essentially undetectable in baseline cm and induction was not seen with PWM or CSF-1. Baseline or "constitutive" expression of BMM and mRNA for CSF-1 and c-kit ligand was seen. Uninduced BMM did not express mRNA for G-CSF, granulocyte-macrophage CSF (GM-CSF), IL-6 or IL-3. CSF-1 induced increased expression of IL-6 mRNA, PWM induced increased expression of G-CSF and IL-6 mRNA and the combination of PWM and CSF-1 induced expression of CSF-1, G-CSF and IL-6 mRNA. Varying levels of CSF-1 had differential effects on cytokine production. Increasing levels of CSF-1 increased IL-6 mRNA and downmodulated CSF-1 mRNA expression. There was a biphasic response of c-kit ligand mRNA expression to CSF-1 exposure; low levels of CSF-1 (50 U/mL) induced, while higher levels (2000 U/mL) inhibited, expression. These data indicate that BMM (and by analogy the macrophage component of Dexter culture stroma), are important sources of CSF-1 and c-kit ligand but not GM-CSF or IL-3. BMM can also be induced to express IL-6 and/or G-CSF. Lastly, CSF-1, by differentially modulating BMM cytokine production in a holocrine or autocrine manner, may function as a central regulator of stromal based hematopoiesis.
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PMID:Cytokine expression from bone marrow derived macrophages. 767 17

Endogenous production of granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), and interleukin-6 (IL-6) was investigated in 10 children who underwent a total of 12 courses of autologous peripheral blood stem cell transplant (PBSCT) by measuring their serum levels using immunoassay kits. The serum G-CSF level increased immediately following infusion of PBSC graft, peaked between days 3 and 7 posttransplant and then declined by the time the granulocyte count rose. No definitive association was found between the continuous high levels of G-CSF and infective episodes, the number of infused nucleated cells, monocytes, CFU-GM, or the number of days required to achieve greater than 0.5 x 10(9)/L granulocyte, greater than 1.0 x 10(9)/L leukocyte, or greater than 50 x 10(9)/L platelet counts. After PBSCT, IL-6 levels tended to be elevated. No detectable serum level of GM-CSF or IL-3 (< 50 pg/mL) was observed before PBSCT and 4 patients showed a transient increase in the GM-CSF level after PBSCT. No significant change was observed in the post-transplant serum levels of IL-3 or M-CSF. The role of endogenously secreted cytokines in early hematopoietic recovery after PBSCT needs further clarification, but, at present, routine use of exogenous G-CSF therapy is not recommended.
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PMID:Granulocyte colony-stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage CSF, interleukin-3, and interleukin-6 levels in sera from children undergoing blood stem cell autografts. 767 1

Endogenous cytokines are thought to mediate numerous biologic processes and may account for some adverse effects experienced following the administration of recombinant proteins. This study describes the pattern of endogenous cytokine exposure following high-dose chemotherapy. Blood concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and erythropoietin (EPO) were measured by enzyme-linked immunosorbent assay (ELISA) methods in 68 patients receiving the same ablative chemotherapy regimen (cyclophosphamide, cisplatin, carmustine). Patients were grouped according to cellular support (autologous bone marrow [BM] CSF-primed peripheral blood progenitor cells [PBPCs]) and prescribed growth factor (recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor [rHuG-CSF or rHuGM-CSF]). Leukocyte reconstitution was most accelerated in the groups treated with PBPCs and rHuG-CSF. IL-6, M-CSF, and TNF-alpha concentrations were higher in the groups treated with rHuGM-CSF and without PBPCs. Maximal endogenous cytokine concentrations occurred approximately 12 days after BM reinfusion. High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42%. High M-CSF and IL-6 levels were associated with increased platelet transfusion requirements. Concentrations of all four cytokines were significantly higher in patients experiencing renal or hepatic toxicity, with elevations occurring in a predictable sequence and M-CSF elevations occurring first. This report shows that endogenous cytokine concentrations may be influenced by either cellular or CSF support and are associated with differences in platelet reconstitution and organ toxicity.
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PMID:Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. 768 20

To study the role of different cytokine combinations on the proliferation and differentiation of highly purified primitive progenitor cells, a serum-free liquid culture system was used in combination with phenotypic and functional analysis of the cells produced in culture. CD34+ CD45RAlo CD71lo cells, purified from umbilical cord blood by flow cytometry and cell sorting, were selected for this study because of their high content of clonogenic cells (34%), particularly multipotent progenitors (CFU-MIX, 12% of all cells). Four cytokine combinations were tested: (1) mast cell growth factor (MGF; a c-kit ligand) and interleukin-6 (IL-6); (2) MGF, IL-6, IL-3, and erythropoietin (Epo); (3) MGF, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-3 fusion protein (FP), macrophage colony-stimulating factor (M-CSF), and granulocyte-CSF (G-CSF); and (4) MGF, IL-6, FP, M-CSF, G-CSF, and Epo. Maximum numbers of erythroid progenitors (BFU-E, up to 55-fold increase) and mature erythroid cells were observed in the presence of MGF, IL-6, IL-3, and Epo, whereas maximum levels of myeloid progenitors (CFU-C, up to 70-fold increase) and mature myeloid cells were found in cultures supplemented with MGF, IL-6, FP, M-CSF, and G-CSF. When MGF, IL-6, FP, M-CSF, G-CSF, and Epo were present, maximum levels of both erythroid and myeloid progenitors and their progeny were observed. These results indicate that specific cytokine combinations can act directly on primitive hematopoietic cells resulting in significant expansion of progenitor cell numbers and influencing their overall patterns of proliferation and differentiation. Furthermore, the observations presented in this study suggest that the cytokine combinations used were unable to bias lineage commitment of multipotent progenitors, but rather had a permissive effect on the development of lineage-restricted clonogenic cells.
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PMID:Cytokine-induced selective expansion and maturation of erythroid versus myeloid progenitors from purified cord blood precursor cells. 768

Oncostatin M (OM) is structurally and functionally related to a subclass of hematopoietic cytokines including leukemia-inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6). Using human endothelial cells (HEC) as a model for cytokine regulation of hematopoietic growth factor expression, we tested OM as an inducer of colony-stimulating activity. Colony-forming cell assays supplemented with culture supernatants from OM-treated HEC contained a threefold increase in colony-forming unit granulocyte-macrophage colonies. Specific immunoassay (enzyme-linked immunosorbent assay) of culture supernatants indicated that OM treatment of HEC resulted in a dose- and time-dependent increase in the accumulation of G-CSF and granulocyte-macrophage CSF (GM-CSF) (> 28-fold). The ED50 for OM induction of G-CSF and GM-CSF protein expression was 17 and 7 pmol/L, respectively. Increased protein expression was associated with a similar increase in steady-state expression of G-CSF and GM-CSF mRNA. Furthermore, a period of 12 to 24 hours elapsed before there were measurable increases in CSF expression, suggesting that OM may stimulate CSF production through a mechanism requiring the synthesis or activation of a secondary mediating factor or pathway. These findings provide the first evidence that OM may regulate myelopoiesis by inducing the cellular expression of hematopoietic growth factors.
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PMID:Regulation of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor expression by oncostatin M. 768 88

To explore the pathogenesis of marrow failure in B-cell type chronic lymphocytic leukemia (B-CLL), we have examined the production of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone marrow (BM) derived from B-CLL patients and their capacity to support hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL stromal cells produced G-CSF and GM-CSF in amounts similar to normal stromal layers, whereas IL-6 production was significantly decreased. Using the blast-colony forming cell assay (BI-CFC) and the classical colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that: (1) marrow stromal cells of B-CLL were able to support only 25% of the BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly was partially corrected by the addition of exogenous IL-6; (3) the colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL stromal cells was lower than that of normal CM; (4) that this was the result of the presence of an inhibitor rather that of a growth factor defect; (5) this inhibition could be abrogated by addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6) this antibody corrected the deficient colony supportive activity of the B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was significantly increased in CLL compared with normal; and (8) that this was not caused by the effect of the B-CLL lymphocytes on the stromal cells. It is concluded that this increased TGF-beta production in B-CLL is probably responsible for the decreased IL-6 production by stromal cells and for the inhibiting activity on hematopoietic precursors as well. We hypothesize that TGF-beta generated at a high level by B-CLL marrow stromal cells could play a major role in the pathophysiology of the BM failure seen in advanced stages of B-CLL.
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PMID:Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production. 769 Dec 58


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