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

The formation of proplatelet-like processes on megakaryocytes cultured in vitro has been shown to be inhibited by prothrombin, found residually in human serum, which is converted in culture to thrombin. This study reports that another factor found in human serum will counter this inhibition and permit proplatelet-like process formation to occur in vitro even in the presence of inhibitory concentrations of thrombin. The factor was purified from human platelet lysates and identified by amino acid sequence analysis as the proteoglycan serglycin. A similar, if not identical, factor was found at elevated levels in the plasma of thrombocytopenic rabbits. Serglycin probably functions as a proplatelet potentiator by virtue of a tendency to complex with thrombin. Thrombin in complex with serglycin retains its enzymatic properties, but is apparently sterically hindered from interacting with the megakaryocyte cell surface. In preliminary studies, the in vivo administration of serglycin in mice resulted in an increased number of circulating platelets when given in combination with interleukin-6 (IL-6).
 ...
PMID:The effect of the platelet-derived glycosaminoglycan serglycin on in vitro proplatelet-like process formation. 833 Jun 53

In humans and nonhuman primates, the in vivo administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) consistently results in marked increase of megakaryocyte ploidy and size similar to that observed with interleukin-6 (IL-6). However, whereas the administration of IL-6 also results in an increase in circulating platelets, there is no predictable corresponding increase in peripheral blood platelets following treatment with rhGM-CSF. To determine whether the failure of rhGM-CSF to produce thrombocytosis is secondary to cytokine-related increased platelet activation and consumption in vivo, we quantified autologous platelet survival time and in vivo platelet activation before and during 5 days of administration of rhGM-CSF to two rhesus monkeys. Platelet survival was measured using autologous platelets labeled with 111Indium-oxine. Platelet activation was assessed by flow cytometric determination of the expression of the major platelet membrane glycoprotein (GP) IIb/IIIa complex, and an activation-dependent epitope on GPIIb/IIIa (recognized by monoclonal antibodies [MABs] LJ-P4 and PAC1, respectively). Platelet activation was also assessed by dose-response aggregometry using adenosine diphosphate (ADP). While megakaryocyte ploidy increased during rhGM-CSF administration, peripheral platelet counts were 418 x 10(9)/L and 525 x 10(9)/L before and 402 x 10(9)/L and 508 x 10(9)/L during cytokine treatment in animals 1 and 2, respectively. No changes were observed in the mean platelet volume. 111Indium-labeled platelet recovery in circulation was similar before (94.7%, 91.8%) and during (92.9%, 92.8%) rhGM-CSF administration, which indicates that cytokine-related in vivo sequestration of platelets does not occur. Autologous platelet survival was 5.6 and 6.2 days before and 5.0 and 5.4 days during the rhGM-CSF treatment (p = 0.07), without significant change in the corresponding platelet turnover rate (derived from the platelet count and survival time). The flow cytometric analysis showed no increase in the binding of either LJ-P4 or PAC1 MABs to the platelet membrane during rhGM-CSF administration. The aggregometry studies demonstrated similar concentrations of ADP inducing half-maximal aggregation (ED50). Overall, the above data indicate that treatment with rhGM-CSF is not associated with in vivo activation, sequestration, or increased consumption of platelets. The data suggest that the failure of rhGM-CSF-stimulated megakaryocytes to increase peripheral platelet count is a manifestation of ineffective megakaryocytopoiesis resulting from inability to increase platelet delivery to the circulation.
 ...
PMID:Effects of recombinant human granulocyte-macrophage colony-stimulating factor on platelet survival and activation using a nonhuman primate model. 840 39

Azidothymidine (AZT) has been demonstrated to increase platelet counts in patients suffering from acquired immunodeficiency syndrome (AIDS). However, the ability of long-term AZT treatment to sustain increases in platelet counts is controversial. We have recently demonstrated that AZT elevates the levels of circulating platelets in both normal C57BL/6 mice and mice made immunodeficient by infection with LP-BM5 murine leukemia virus (MAIDS mice). We therefore studied the effect of long-term AZT administration on platelet formation in both normal and MAIDS mice. Peripheral blood indices, levels of femoral and splenic megakaryocyte colony forming units (CFU-MK), and plasma levels of cytokines important in platelet formation-interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF)--were examined. Platelet counts remained elevated throughout a 120-day AZT treatment period. Splenic CFU-MK were not significantly changed in MAIDS mice, except at day 15 when they were elevated. Splenic CFU-MK were significantly decreased in normal mice at days 8 and 120, and increased at day 30. Bone marrow CFU-MK were increased by AZT treatment at all time points tested in both normal and MAIDS mice. Plasma levels of GM-CSF were unchanged by AZT treatment in both normal and MAIDS mice. Plasma levels of IL-6 were unchanged in AZT-treated normal mice but decreased in AZT-treated MAIDS mice. These results indicate that long-term AZT treatment maintains elevated levels of platelets in both normal and MAIDS mice and affects CFU-MK colony formation. Our studies add to a growing body of work suggesting that AZT can ameliorate thrombocytopenia associated with HIV disease.
 ...
PMID:Sustained elevation of platelet counts by long-term azidothymidine treatment of immunosuppressed mice. 845 34

To further investigate the thrombopoietic and adverse effects of interleukin-6 (IL-6), 2 or 10 micrograms/day of recombinant human (rh) IL-6 was administered intraperitoneally (i.p.) to mice for up to 30 days. IL-6 increased platelet count, which plateaued at a level 30 to 40% higher than control after 5 days of treatment. This cytokine also maintained the high platelet count for the duration of treatment. The count exceeded normal levels 7 days after cessation of the 30-day treatment. IL-6 also induced a remarkable increase in the size but not the frequency of megakaryocytes in bone marrow sections. The number of bone marrow colony-forming units megakaryocyte (CFU-MK) and colony-forming units granulocyte-macrophage (CFU-GM) was not augmented by the administration of IL-6 in this protocol, while spleen progenitors were significantly stimulated. Small but significant increases did occur in the number of bone marrow megakaryocytes and CFU-MK, and in the proportion of CFU-MK in the DNA synthetic phase in mice treated with 10 micrograms/day of IL-6 for 30 days. Electron microscopic examination of bone marrow demonstrated that IL-6 remarkably developed the distribution of the demarcation membrane system (DMS) in mice treated for 30 days, with little change in mice treated for 5 days. The administration of 2 micrograms/day for 30 days induced a 2.2-fold increase in fibrinogen. No changes were observed in the hepatic or renal functions. Histologic and immunofluorescence studies on the kidneys revealed no significant changes compared with controls, indicating that proliferation of the glomerular mesangium did not occur. No neutralizing antibodies were detected in mice treated for 30 days. We conclude that the long-term administration of IL-6 in mice stimulates megakaryocyte maturation and platelet production with few adverse effects, and that this cytokine may be a candidate for the treatment of thrombocytopenia in humans.
 ...
PMID:Thrombopoietic effects of interleukin-6 in long-term administration in mice. 851 64

Prolonged thrombocytopenia complicated by bleeding episodes represent a major problem following autologous bone marrow transplantation (ABMT). Recombinant human interleukin-6 (rhIL-6) has been shown to be a maturation factor for both mouse and human megakaryocytes. We administered rhIL-6 to a 43 year old woman who developed marked resistant and prolonged thrombocytopenia with bleeding episodes following autologous peripheral blood stem cell transplantation (APBSCT). Twenty days after the initiation of rhIL-6 therapy, the number of megakaryocyte (MK) progenitors (CFU-MK and BFU-MK) cultured from the peripheral blood increased followed by a moderate increase in the number of bone marrow megakaryocytes. The platelet count increased and the bleeding episodes disappeared. Although spontaneous platelet recovery cannot be ruled out in this case it seems that rhIL-6 may be an important thrombopoietic factor for severe thrombocytopenia following APBSCT.
 ...
PMID:Recombinant human interleukin-6 accelerates in-vitro megakaryocytopoiesis and platelet recovery post autologous peripheral blood stem cell transplantation. 853 29

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.
 ...
PMID:Stimulation of thrombopoiesis in mice by fibroblast growth factor 9. 861 24

We investigated megakaryocytic differentiation in a newly-established Ph1-positive leukemic cell line, MC3, which showed tri-lineage immunophenotypes (myeloid antigens2+, CD19(1+) and CD41a1+) and was positive for CD34 and CD38. TPA induced MC3 cells to differentiate to an early stage of megakaryocyte lineage exhibiting an increase in the expression of platelet glycoproteins (GP) IIb/IIIa (CD41a), and an increase in cell size and nuclear ploidy. TPA treatment also enhanced the expression of GPIIb mRNA, and induced the expression of interleukin-6 (IL-6) and its receptor mRNAs, while it did not induce transcripts of the genes IL-11 and mpl ligand, and further decreased the transcript of the mpl gene. Consistent with these findings, MC3 cells treated with TPA showed an increased expression of GATA-1, but not GATA-3 transcripts, whereas those without TPA treatment expressed only the GATA-2 transcript. These results provide an insight into the study for the regulatory mechanism of megakaryocytopoiesis and leukemic cell differentiation.
 ...
PMID:Megakaryocytic differentiation of a leukemic cell line, MC3, by phorbol ester: induction of glycoprotein IIb/IIIa and effects on expression of IL-6, IL-6 receptor, mpl and GATA genes. 863 63

We demonstrated bundle formation of microtubules both in the cytoplasmic processes and in the cytoplasm near the nucleus of cultured megakaryocytes by means of electron and immunofluorescent microscopy. To determine whether this bundle formation was related to megakaryocyte maturation, we studied the effects of recombinant human interleukin-6 (rhIL-6) in vitro and in vivo on this event. About 75% of the megakaryocytes in the bone marrow had no fibrous microtubule structures in the cytoplasm (type I), and about 25% had bundles of microtubules (type II). The formation of these bundles was promoted by rhIL-6 both in vitro and in vivo. Considerably more megakaryocytes cultured with recombinant murine (rm) IL-3 and rhIL-6 became type II than those cultured with rmIL-3 alone. Megakaryocytes from mice given rhIL-6 (10 microg/animal/d) subcutaneously also began to form bundles in proportion to an increase in platelet counts. After the administration of rhIL-6, about half of the megakaryocytes contained microtubule bundles in their cytoplasm. These results indicate that microtubule-bundle formation is one maturational event in megakaryocyte development and that rhIL-6 could accelerate this event.
 ...
PMID:A novel aspect of the maturational step of megakaryocytes in thrombopoiesis: bundle formation of microtubules in megakaryocytes. 864 55

To determine the frequencies and differential counts of megakaryocytes after cytoreductive treatment in nucleated low-density (1.060 g/ml) bone marrow cells (BMNC) of dogs an immunogold-silver staining (IGSS) technique with the lineage specific monoclonal antibody 2F9 was established. This antibody recognizes the glycoprotein IIb/IIIa complex expressed on the surface of canine megakaryocytes and platelets. The IGSS technique enables not only the detection of megakaryocytes occurring at a low frequency (0.1-0.2%), but also the discrimination between the different maturation stages of megakaryocytes due to cell size, nuclear morphology and cytoplasmic staining. By the use of this technique, small lymphoid megakaryocytic cells were identified. Comparable numbers of megakaryocyte colony-forming cells in 2F9-depleted and nondepleted BMNC suspensions (25.7 +/- 5.0 vs. 25.3 +/- 5.1 Meg-CFC/10(5) BMNC) indicate that these small 2F9 positive cells are nonclonogenic precursors of megakaryoblasts. To prove the applicability of IGSS, serial examinations of bone marrow samples from dogs treated with recombinant human interleukin-6 (IL-6) after exposure to 2.4 Gy total body irradiation (TBI) were performed. The results of the microscopic evaluation indicate that, in the recovery phase after TBI, IL-6 induced an earlier and stronger increase in megakaryocyte frequency in comparison to the control. Interestingly, all maturation stages of the megakaryocytic lineage took part in this IL-6 induced improvement of megakaryocyte recovery.
 ...
PMID:Investigation of megakaryopoiesis in myelosuppressed bone marrow using immunogold-silver staining (IGSS). 864 3

It is known that platelet alpha-granule constituents including platelet-derived growth factor (PDGF), platelet factor 4 (PF4) and transforming growth factor-beta (TGF-beta) can affect megakaryocytopoiesis. Serotonin, a platelet dense granule constituent has been shown to have a mitogenic effect on fibroblasts and smooth muscle cells but whether it has the same effect on megakaryocytes remains unclear. In this study, we investigated the effect of serotonin on megakaryocytopoiesis and the possible mechanism of its effect using the mouse plasma clot culture method. The results show that: (a) serotonin significantly stimulates megakaryocyte colony formation with maximum stimulation at 100 nM; (b) enhanced action is found between serotonin and interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin (EPO) and PDGF; (c) ketanserin, a 5-HT2 receptor antagonist, blocks the mitogenic effect of serotonin on megakaryocytopoiesis; and (d) Meg-01 cells (a megakaryocyte cell line) express 5-HT2 receptors. This study demonstrates that serotonin has a mitogenic effect on megakaryocytopoiesis and this effect may be mediated via the 5-HT2 receptor which is known to be coupled to G protein. It is suggested that serotonin may also be involved in the feedback control of megakaryocytopoiesis.
 ...
PMID:Serotonin stimulates megakaryocytopoiesis via the 5-HT2 receptor. 873 1


<< Previous 1 2 3 4 5 6 7 8 9 Next >>