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)

Retrovirus-mediated gene transfer into human hematopoietic stem cells has been proposed as a means of therapy for various inherited diseases and as a method of gene marking. The transduction efficiency of an amphotropic retroviral vector (PA317/HyTK) containing a hygromycin phosphotransferase-thymidine kinase fusion gene was examined with human CD34+ bone marrow cells in the presence of interleukin-3 (IL-3), interleukin-6 (IL-6), and stem cell factor. Transduction efficiencies determined from the ability of transduced granulocyte-macrophage colony forming units (CFU-GM) to grow in hygromycin B and from polymerase chain reaction analysis of individual transduced CFU-GM growing in the presence of hygromycin B were 0.3-3.0% (mean +/- S.D., 1.1 +/- 0.9%) and 0.1-1.2% (mean +/- S.D., 0.5 +/- 0.4%), respectively. Ganciclovir at a dose of approximately 1 microM reduced the number of CFU-GM derived from vector-infected CD34+ cells by 50%. These findings demonstrate that human hematopoietic stem cells infected with this retroviral vector are susceptible to ganciclovir, offering the potential to control transduced gene expression in vivo.
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PMID:Retrovirus-mediated transfer of a hygromycin phosphotransferase-thymidine kinase fusion gene into human CD34+ bone marrow cells. 753 98

Monocytes have recently been recognized as a precursor of Langerhans cells. This study examined the regulatory influence of the epithelial environment on the putative first step of the transition towards a Langerhans cell phenotype--the induction of CD1a antigen. The keratinocyte-derived cytokines granulocyte-macrophage-colony-stimulating factor, tumour necrosis factor-alpha, interleukin-6, and interleukin-1 beta induced CD1a expression, as did supernatants of keratinocytes extracted from inflammatory sites (periodontitis). Induction was abrogated by transforming growth factor-beta and a keratinocyte-derived interleukin-1 inhibitor. The optimal temperature for induction was 34 degrees C, not 37 degrees C. These results demonstrate that the components of the epithelial environment (cytokines and lower temperature) exert important influences, which may be part of local regulation of Langerhans cell development.
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PMID:Induction of the CD1a Langerhans cell marker on human monocytes. 754 Aug 33

The bone marrow microenvironment consists of stromal cells and extracellular matrix components which act in concert to regulate the growth and differentiation of hematopoietic stem cells. There is little understanding of the mechanisms which modulate the regulatory role of stromal cells. This study examined the hypothesis that mesenchymal growth factors such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) modulate stromal cell activities and thereby influence the course of hematopoiesis. Both bFGF and EGF were potent mitogens for marrow stroma. However, both factors proved to be inhibitory to hematopoiesis in primary long-term marrow cultures. Inhibition was also observed when hematopoietic cells and bFGF or EGF were added to subconfluent irradiated stromal layers, demonstrating that the decline of hematopoiesis was not due to overgrowth of the stromal layer. Loss of hematopoietic support in bFGF and EGF was dose-dependent. Removal of bFGF and EGF permitted stromal layers to regain their normal capacity to support hematopoiesis. In stroma-free long-term cultures, neither factor affected CFU-GM expansion. Basic FGF slightly enhanced granulocyte-macrophage colony forming unit (CFU-GM) cloning efficiency in short-term agarose culture. Basic FGF did not reduce the levels of interleukin-6 (IL-6), GM-CSF, or G-CSF released by steady state or IL-1-stimulated stroma. Similarly, the constitutive levels of steel factor (SF) mRNA and protein were not affected by bFGF. Basic FGF did not alter the level of TGF-beta 1 in stromal cultures. We conclude that bFGF and EGF can act as indirect negative modulators of hematopoietic growth in stromal cultures. The actual mediators of regulation, whether bound or soluble, remain to be identified.
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PMID:Basic fibroblast growth factor and epidermal growth factor downmodulate the growth of hematopoietic cells in long-term stromal cultures. 759 17

Hemopoietic aplasia is the primary limitation of drug and radiation cancer therapies. We have previously demonstrated that, individually, both interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) can accelerate recovery from radiation-induced hemopoietic aplasia. In vitro studies suggest that IL-6 affects cells early in the hemopoietic hierarchy, while G-CSF affects more committed progenitor cells. Because these cytokines may also affect different cell populations in vivo, we hypothesized that the use of these agents in combination may further enhance recovery from hemopoietic aplasia. Female B6D2F1 mice were exposed to a high sublethal 7.75 Gy dose of 60Co radiation. Following irradiation, mice were administered subcutaneous injections of either saline, 500 micrograms/kg of recombinant human IL-6 once daily on days 1-6, 125 micrograms/kg of recombinant human G-CSF once daily on days 1-17, or both cytokines as described. Peripheral white blood cell (WBC), red blood cell (RBC), and platelet (PLT) counts, as well as femoral and splenic granulocyte-macrophage colony-forming cell (GM-CFC) and day-12 spleen colony-forming unit (CFU-S) contents were evaluated on days 7, 10, 14, 17 and 21 postirradiation. IL-6 treatment alone slightly accelerated postirradiation recovery of most hemopoietic parameters, while G-CSF treatment dramatically enhanced recovery of all hemopoietic parameters evaluated. Co-administration of IL-6 and G-CSF further enhanced the hemopoietic recovery. The most notable effects in combination-treated mice were on recoveries of bone marrow and splenic CFU-S, which were significantly enhanced above those in G-CSF-treated irradiated mice as early as day 10 postirradiation. Although by day 14 postirradiation, splenic GM-CFC and CFU-S recoveries in both G-CSF- and combination-treated mice had surpassed unirradiated control values, combination-treated mice exhibited a greater overshoot. These studies demonstrate the ability of IL-6 treatment to enhance G-CSF-mediated acceleration of multilineage recovery following radiation-induced hemopoietic aplasia.
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PMID:Effects of combined administration of interleukin-6 and granulocyte colony-stimulating factor on recovery from radiation-induced hemopoietic aplasia. 767 16

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

The effects of direct activators of protein kinase C (PKC) (the phorbol ester tetradecanoyl phorbol myristic acid [TPA] or bryostatin) on the ability of a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) to proliferate and develop in soft agar was assessed. In the absence of colony stimulating factors, the PKC activators did not stimulate colony formation. However, in the presence of optimal concentrations of granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6), TPA or bryostatin markedly elevated the number of colonies formed from the GM-CFC. In the absence of TPA, IL-6, and G-CSF, respectively, both stimulated the formation of about 3% of the colonies observed when IL-3 was present. When TPA plus G-CSF or IL-6 were added together, this figure increased to 48% and 54%, respectively. In both instances, the types of mature cells formed was altered from colonies of mature neutrophilic cells to a mixture consisting predominantly of macrophages with some neutrophils. Similar results were observed when bryostatin replaced TPA in these assays. When single cell colony-forming assays were performed, the same results were obtained. The presence of G-CSF, or IL-6, and the activator of PKC used (TPA or bryostatin) was required throughout the colony-forming assay for an optimal synergistic effect to be observed. These data indicate that agents that activate PKC can promote the proliferation and development of GM-CFC via a synergistic interaction with G-CSF or IL-6. Furthermore, there is an apparent role for PKC in development and possibly lineage commitment of GM-CFC.
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PMID:Protein kinase C activators can interact synergistically with granulocyte colony-stimulating factor or interleukin-6 to stimulate colony formation from enriched granulocyte-macrophage colony-forming cells. 767 6

Present methods for long-term hematopoietic culture (LTHC) employ a static culture environment which is not well-characterized. Primitive long-term culture-initiating cell (LTC-IC) numbers have been shown to decline in conventional static human LTHC, even with exogenous cytokine combinations. We have expanded human hematopoietic cells from umbilical cord blood on a preformed marrow stroma with synergistic cytokine combinations in a novel perfusion bioreactor system, which continuously maintained culture conditions within desired ranges. Interleukin-3 (IL-3) and interleukin-6 (IL-6) in perfusion culture resulted in rapid 7-day expansion of granulocyte-macrophage colony forming units (CFU-GM, 11-fold), erythroid burst-forming units (BFU-E, 2.5-fold), and granulocyte-erythroid-macrophage colony forming units (CFU-Mix, 2.4-fold), compared to 6-fold, 1.4-fold, and no expansion, respectively, in static cultures. Addition of stem cell factor (SCF) to IL-3/IL-6 in static culture increased the extent of CFU-GM expansion (to 9-fold), but did not result in BFU-E or CFU-Mix expansion. In perfusion cultures with IL-3/IL-6/SCF, much greater expansions of CFU-GM (18-fold) and CFU-Mix (5.3-fold) were obtained. More importantly, expansion of LTC-IC (nearly 3-fold in two of three experiments) was only obtained with IL-3/IL-6/SCF and perfusion. The ability to expand hematopoietic cells while maintaining or expanding primitive progenitors has potential clinical applications in bone marrow transplantation and gene therapy.
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PMID:Expansion of primitive human hematopoietic progenitors in a perfusion bioreactor system with IL-3, IL-6, and stem cell factor. 768 Feb 9

To investigate the functional change of stromal cells along with differentiation, we used a differentiation-inducible mouse embryo fibroblast cell line, C3H10T1/2 (10T1/2). Stably determined preadipocyte and myoblast cell lines were established after a brief exposure of 10T1/2 cells to 5-azacytidine. These cell lines terminally differentiated into adipocytes and myotubes, respectively, under appropriate conditions. The hematopoiesis-supporting ability of each 10T1/2-derived cell line was examined by coculture with FACS-sorted murine hematopoietic stem cells (Thy-1lo c-kit+ Lin-). The number of granulocyte-macrophage progenitors (CFU-GM) was slightly reduced after 7 days of culture with parent 10T1/2 fibroblasts, whereas a marked increase in CFU-GM number was observed when the cells were cultured on preadipocytes. Mature adipocytes and myogenically determined cell lines, on the other hand, did not support CFU-GM growth. Further, Northern analysis showed that the preadipocyte cell line acquired the ability to produce a significant amount of stem cell factor (SCF), interleukin-6 (IL-6), leukemia inhibitory factor, and macrophage colony-stimulating factor mRNAs in response to IL-1 or lipopolysaccharide stimulation. Terminal adipocytic differentiation resulted in reduced ability to express these cytokine mRNAs. Similarly, highest IL-6 activity was detected in the supernatant of preadipocyte culture, whereas adipocytes did not secrete IL-6 even after IL-1 stimulation. Interestingly, hematopoiesis-nonsupporting myoblasts and myotubes also expressed abundant SCF mRNA, suggesting that SCF, per se, may not be sufficient for stem cell growth and survival. The 10T1/2-derived cell lines could provide a valuable tool to aid in the analysis of stromal cell development and the search for novel stromal factors.
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PMID:Changes in hematopoiesis-supporting ability of C3H10T1/2 mouse embryo fibroblasts during differentiation. 768 Feb 42

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


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