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)

Data concerning megakaryocytopoiesis and its regulation were summarized in this report. Critical analysis of these data indicates that: (i) megakaryocytopoiesis is a complex, multiple-stage cellular and biologic process; (ii) the survival, proliferation and differentiation of progenitor cells into immature megakaryocytes are regulated mainly by interleukin-3, granulocyte-macrophage colony-stimulating factor and an as yet uncharacterized megakaryocyte colony-stimulating factor, and the maturation of immature megakaryocytes to produce platelets is regulated primarily by interleukin-6 and thrombopoietin; (iii) optimal megakaryocyte development needs adequate interactions of several growth factors with target cell population and hematopoietic microenvironment; (iv) megakaryocytopoietic inhibition is controlled essentially by megakaryocyte-platelet products such as transforming growth factor-beta, and platelet factor 4 and its related proteins; interferon-alpha and -gamma also are able to play an inhibitory role; and (v) expansion or decrease of either normal or neoplastic megakaryocyte progenitor cells, change of platelet mass and abnormalities of growth factor levels in hematopoietic tissue might result in an abnormal megakaryocytopoiesis.
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PMID:Megakaryocytopoiesis: characterization and regulation in normal and pathologic states. 195 49

The gene of thrombopoietin (TPO) has been cloned and identified to be identical to gene of the c-mpl ligand. It is known that the mRNA of TPO is expressed in liver and kidney. However, it is not clarified which cells in the liver produce TPO. Using a human hepatoma cell line, HepG2, we demonstrated that the TPO mRNA was expressed by liver parenchymal cells without any stimulation. To clarify the regulation of the expression of the TPO mRNA in HepG2 cells by cytokines, we assessed the effects of 5 cytokines, transforming growth factor-beta 1, activin A, platelet-derived growth factor, hepatocyte growth factor, and interleukin-6. These cytokines have no significant regulative effect on the expression of the TPO mRNA in HepG2 cells. Our results suggest that liver parenchymal cells may be the TPO producing cells and also suggest that some hepatoma cells may produce TPO constitutively.
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PMID:Constitutive expression of the thrombopoietin gene in a human hepatoma cell line. 750 24

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.
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PMID:A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. 753 15

Previously, it was believed that megakaryocytopoiesis was regulated by two types of humoral factors: megakaryocyte colony-stimulating factor (MK-CSF), which acts on progenitors inducing their proliferation, and thrombopoietin (TPO), a megakaryocyte(s) (MK) maturational factor that induces platelet formation. The recently cloned Mpl-ligand (Mpl-L) seems to have both properties in vivo and in vitro and has also been called TPO. However, it cannot be excluded that a part of these activities is due to a synergistic effect with growth factors present in the serum or synthesized by accessory cells. To delineate the precise TPO (Mpl-L) biologic activities, we performed serum-free cultures at limiting cell dilution. Target cells were adult human marrow CD34+CD41+ cells, which represent a highly selected population of late MK progenitor or transitional cells. Cells were purified using a flow cytometer equipped with an automatic cloning design unit. We determined that the recombinant molecule had a biologic activity that reached a plateau at 10 ng/mL. At this concentration, a linear relationship between the average MK number per well and the number of cells seeded (between 1 to 50 cells per well) was observed. At one cell per well, 60% of the wells contained a single MK at day 5 of culture. Half of these wells contained only one large MK, whereas the other half contained several MK (up to 25), demonstrating that TPO has direct proliferative biologic activity. In contrast, at limiting dilution, none of the other cytokines tested (stem cell factor [SCF], interleukin-6 [IL-6], and erythropoietin [Epo]) were effective, whereas IL-3 showed a mild effect. However, a combination of SCF plus IL-6 plus IL-3 produced similar results as TPO alone. Addition of the other cytokines to TPO did not enhance the cloning efficiency of the CD34+CD41+ cells but increased twofold the average number of MKs per clone. MKs reached a ploidy of 32N and 64N in the presence of TPO. The mean ploidy value was approximately 6 and was not modified by addition of the other cytokines. At the ultrastructural level, a majority of the MKs showed maturational defects related to an imbalance between the synthesis of alpha-granules and demarcation membranes. However, a fraction (about 30%) had a cytoplasmic maturation that exactly mimicked that of marrow MKs. In addition, proplatelet-shedding MKs were observed in the cultures, even at limiting dilution. Such a result was not observed with any other individual cytokines, including the combination of three cytokines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The Mpl-ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. 754 60

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

Fibroblast growth factor 9 (FGF-9), a novel member of the FGF family, was found to have thrombopoietic activity in vitro and in vivo. In an in vitro megakaryocyte colony-stimulating factor assay, anti-mouse interleukin-6 (IL-6) monoclonal antibody neutralized FGF-9 activity. This suggests that the activity may be exerted via IL-6 induction. BALB/c mice that received subcutaneous FGF-9 injections of 4 to 100 micrograms/day for 2 weeks showed a dose-dependent transient increase in peripheral platelet counts 10 to 12 days after the first treatment. Histologic studies showed a marked increase in megakaryocytes in bone marrow and extramedullary hematopoiesis in the spleen and the liver. Examination of changes in the DNA content of bone marrow megakaryocytes revealed that the ploidy distribution underwent a marked shift 3 days after FGF-9 injection, with a large increase in the 2N megakaryocyte population. The major modal ploidy shifted from the normal 16N to 2N. The number of megakaryocyte progenitor cells in FGF-9-treated mice increased up to 1.5-fold in the bone marrow and 10-fold in the spleen on day 6. These results indicate that FGF-9 acts on the in vivo proliferation of megakaryocytes.
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PMID:Stimulation of thrombopoiesis in mice by fibroblast growth factor 9. 861 24

Microvascular thrombosis and free flap failure are complications of free tissue transfer for coverage of lower extremity soft-tissue and bony defects despite appropriate vessel selection and adherence to meticulous technique. Increased rates of flap failure have been associated with reconstruction performed between 3 days and 6 weeks after injury, as well as in patients with thrombocytosis. We have found that serum platelet levels rise significantly after lower extremity injury. It is our theory that a circulating mediator or cytokine is released in response to injury, inducing the thrombocytosis. Twenty-one patients with Gustilo grade IIIb and IIIc injuries were studied prospectively. Serum was collected throughout the postinjury period. Platelet count, leukocyte count, hemoglobin concentration, and hematocrit were determined. Samples were also subjected to a platelet aggregation study as well as enzyme-linked immunosorbent assay for interleukin-3, interleukin-6, interleukin-11, and granulocyte macrophage-colony-stimulating factor. Megakaryocyte growth and development factor enzyme-linked immunosorbent assay and a myleoproliferative leukemia virus-transfected cell line assay for thrombopoietin were performed. Bone marrow was studied with flow cytometric analysis. Mean initial platelet count was 196,000 per cubic millimeter. There was an initial 26% decline to 140,000 per cubic millimeter, followed by an increase to 361% of baseline on day 16. No significant variations in serum leukocyte count or hemoglobin concentration were seen. Spontaneous and induced platelet aggregation responses were normal. Interleukin-6 was detected at elevated levels. However, interleukin-3, interleukin-11, granulocyte macrophage-colony-stimulating factor, and thrombopoietin were not measurable. Marked megakaryocytosis was seen on bone marrow analysis. Interleukin-6 may, therefore, play a role in the mechanism of thrombocytosis. We suggest that because patients with complex bony injuries of the leg experience platelet elevations that peak approximately 2 weeks after injury, microvascular free flap reconstructions should be considered high risk during this time period.
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PMID:Thrombocytosis after major lower extremity trauma: mechanism and possible role in free flap failure. 874 59

Thrombopoietin (TPO), the ligand for the c-Mpl cytokine receptor, is a recently identified cytokine with potent effects on platelet production. The receptor-binding portion of c-Mpl ligand is encompassed in another molecule known as megakaryocyte growth and development factor, or MGDF. Although it is clear that the administration of TPO or MGDF to animals dramatically increases the platelet count, the specific stage(s) of thrombopoiesis during which these molecules are principally active have not been unambiguously determined. Pharmacology studies administering MGDF at doses ranging from 0.1 to 630 micrograms/kg/d to mice revealed a biphasic response in platelet production. Administration of the drug at concentrations from 6 to 60 micrograms/kg/d resulted in platelet counts 5-fold above normal. However, doses > 60 micrograms/kg/d resulted in less-than-optimal platelet production. This phenomenon was investigated in vitro. Using an established culture system for the generation of human megakaryocytes and platelets, MGDF was shown to be optimally and equivalently active in the generation of mature megakaryocytes at concentrations from 10 to 1000 ng/ml. However, the cytokine was not required for proplatelet formation and in fact was inhibitory to that process in a dose-dependent manner. When MGDF was added to human megakaryocytes at concentrations of 200 ng/ml or greater, proplatelet formation was inhibited to 30% of control values. MGDF-mediated inhibition was specific, since the addition of the truncated form of the c-Mpl receptor reversed the inhibition in a dose-dependent manner. Other recombinant factors, interleukin-6, interleukin-11 and erythropoietin had no significant positive or negative effects in this human proplatelet assay. Together, these data suggest that although TPO and MGDF promote the full spectrum of megakaryocyte growth and development, they are not necessary for proplatelet formation, and may in part regulate platelet shedding by their absence.
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PMID:The role of megakaryocyte growth and development factor in terminal stages of thrombopoiesis. 890 74

Autologous blood transfusion is advantageous in that it eliminates the risk of transfusion-transmitted infection or complications caused by the immune reaction. Increased platelet counts after repeated phlebotomy are commonly observed. This study was carried out to clarify the mechanism of increased platelets during preoperative autologous blood donation. Eleven patients of elective surgery in which is in good preoperative condition and there is no emergency were selected for this study. Blood cell counts, platelet size distribution(PDW, MPV, P-LCR) and serum concentration of erythropoietin(EPO), interleukin-3(IL-3) and interleukin-6(IL-6)were measured. A transient increase in platelet was seen in almost patients during preoperative autologous blood donation. No marked changes in platelet size distribution and serum concentration of EPO, IL-3 and IL-6. These results suggest that increased platelet counts during preoperative autologous blood donation might be caused by some specific cytokines related to megakaryocyte differentiation such as c-MPL ligand.
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PMID:[Analysis of mechanism of increased platelet counts during preoperative autologous blood donation]. 902 46

The effects of thrombopoietin (TPO; c-mpl ligand), FLT3/FLK-2 ligand (FL), and interleukin-6 (IL-6) on the survival of murine hematopoietic long-term reconstituting cells (LTRC) were studied by using lineage-negative, Sca-1-positive, c-kit-positive (Lin-Sca-1(+)c-kit+) marrow cells from 5-fluorouracil-treated mice. We tested the ability of these cytokines to maintain the viability of LTRC by transplanting the cultured cells to lethally irradiated Ly-5 congenic mice together with compromised marrow cells. As a single agent, only TPO could maintain the LTRC. Neither IL-6 nor FL was effective by itself, but they acted synergistically to maintain the LTRC. We examined whether the maintenance of LTRC by these cytokines was due to the survival of stem cells or was the result of active cell divisions and self-renewal. To monitor cell division, we used membrane dye PKH26. Enriched cells were stained with PKH26 on day 0 and incubated in suspension culture with TPO or with IL-6 and FL for 7 days. On day 7, PKH26(low) and PKH26(high) cells were prepared by sorting and their in vivo reconstituting abilities were tested by transplantation into lethally irradiated Ly-5 congenic mice together with compromised marrow cells. PKH26(high) populations cultured with both TPO alone and the combination of IL-6 and FL showed greater reconstitution activity than that of PKH26(low) populations. These data indicate that TPO alone and the combination of IL-6 and FL can support the survival of stem cells without stimulating their active cell proliferation.
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PMID:Thrombopoietin promotes the survival of murine hematopoietic long-term reconstituting cells: comparison with the effects of FLT3/FLK-2 ligand and interleukin-6. 965 44


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