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)

Previous work showed that mice treated with platelet-specific antiserum prior to whole-body irradiation did not suffer the degree or duration of thrombocytopenia as did irradiated control mice. We now report that a partially purified preparation of a thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) mimics the biological effects of platelet-specific antiserum treatment in hematopoietically suppressed mice. Male C3H mice were exposed to 3.0 or 4.5 Gy of 137Cs gamma radiation and injected with a total dose of 4 units (U) of TSF. Human serum albumin (HSA) and rabbit anti-mouse platelet serum-injected mice, along with unirradiated mice, served as controls. Packed cell volumes (PCV), RBC counts, WBC counts, platelet counts, and percentage 35S incorporation into platelets were measured in mice at various days (7-14) following treatment. The results showed that irradiated mice treated with TSF had increased 35S uptake into platelets and higher platelet counts than HSA-treated controls. Also, PCV, RBC counts, and WBC counts of irradiated mice treated with TSF were significantly higher than values for HSA-treated mice. Additional experiments using 40,000 U/mouse of Interleukin-6 (IL-6), 227 U/mouse of granulocyte macrophage-colony stimulating factor (GM-CSF), or a combination of GM-CSF and IL-6 did not show increased platelet counts or 35S incorporation into platelets on Days 10 and 14 when compared to other mice treated with control substances. These results suggest that the radioprotective effects of platelet antibodies reported previously may be due to the release and action of thrombopoietin. These studies also demonstrate that thrombopoietin therapy will modulate the severe thrombocytopenia that occurs in radiation-induced bone marrow suppression.
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PMID:Thrombopoietin from human embryonic kidney cells causes increased thrombocytopoiesis in sublethally irradiated mice. 141 Feb 78

Thrombopoietin or thrombocytopoiesis-stimulating factor (TSF) is known to be the natural stimulator of megakaryocytopoiesis and, thus, stimulates thrombocytopoiesis. In the past 15 years, new assay technology and sources of the hormone have made possible partial characterization of the molecule and clarification of the biologic role of thrombopoietin. Experiments describing the biology and characterization of TSF are reviewed. In addition, a brief history of the molecule, its biology, and the effects of thrombopoietin on both thrombocytopoiesis and megakaryocytopoiesis are discussed, including the effects of thrombopoietin on platelet counts, platelet sizes, and incorporation of isotopes. In the discussion of thrombopoietin's control of megakaryocytopoiesis there is specific information showing that thrombopoietin stimulates an increase in megakaryocyte size and number, DNA content, endomitosis, and maturation. Thrombopoietin also increases the number of early precursor cells of the megakaryocytic series, that is, small acetyl-cholinesterase-positive cells. New information is given on the chemistry of thrombopoietin, along with present assays and the relationship of thrombopoietin to interleukin-6. The clinical aspects of thrombopoietin, with detailed descriptions of several disease states in which decreases and excesses of the hormone have been found, are presented. The potential uses of thrombopoietin in clinical medicine are reviewed. In the near future, it appears that successful gene cloning of the hormone will be achieved, which will allow production of large amounts of recombinant thrombopoietin. The pure material will be helpful in clarifying the hormone's mode of action. Thrombopoietin will no doubt prove to be useful in treating patients with various hematologic disorders, such as patients undergoing bone marrow transplantation, chemotherapy, or radiotherapy, and other patients with various types of marrow hypoplasia.
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PMID:Thrombopoietin. Its biology, clinical aspects, and possibilities. 155 Feb 68

The induction of thrombocytopenia results in elevated levels of thrombopoietin (TPO), which can be detected in the plasma of experimental animals. Acute, severe thrombocytopenia (platelet count less than 5% of control) was produced in mice by the administration of either guinea pig or rabbit antimouse platelet antiserum. Control mice received equal volumes of normal serum. At various times after the induction of thrombocytopenia (0.5, 1, 2, 3, 4, 6, 12, and 24 hours) citrated plasma was collected, and circulating interleukin-6 (IL-6) levels were measured using the IL-6-dependent murine hybridoma cell line B9. At no time points after induction of thrombocytopenia were plasma IL-6 levels significantly different from control animals that received normal serum. However, injection of heterologous serum did result in slightly elevated plasma IL-6 levels (at 2 and 3 hours) compared with basal levels measured in uninjected animals. This brief increase was not related to the production of thrombocytopenia. Protein fractions from the plasma of thrombocytopenic rabbits were also tested for the presence of IL-6. Preparations that contained TPO, as shown by stimulation of megakaryocyte maturation in vitro, did not contain detectable levels of IL-6. The ability of the B9 assay to detect the elevation of IL-6 levels in murine or rabbit plasma was verified after the administration of bacterial endotoxin, which is known to increase circulating IL-6 concentrations. IL-6 levels were highly elevated in rabbit or mouse serum after the administration of 5 mg/kg or 1 mg/kg of endotoxin, respectively. Anti-IL-6 antiserum did not neutralize the in vitro megakaryocyte maturation activity of partially purified TPO from the plasma of thrombocytopenic rabbits. In addition, IgG purified from the same antiserum did not neutralize partially purified TPO, as shown after incubation with TPO and subsequent precipitation with agarose-bound protein A. These results show that, unlike TPO, levels of IL-6 do not increase after the induction of acute, severe thrombocytopenia, and strongly suggest that IL-6 does not mediate the thrombopoietic response to acute thrombocytopenia. Although prolonged administration of IL-6 has been shown to induce thrombocytosis, IL-6 and TPO are apparently different and immunologically distinct molecules.
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PMID:Evidence that interleukin-6 does not play a role in the stimulation of platelet production after induction of acute thrombocytopenia. 162 96

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

A thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) derived from human embryonic kidney (HEK) cells is known to increase platelet production and to increase the number of morphologically unrecognizable early megakaryocytes, ie, small acetylcholinesterase-positive (SAChE+) cells in mice. Other recent studies have concluded that interleukin-6 (IL-6) also stimulates murine megakaryocytopoiesis both in vitro and in vivo. Some workers have suggested that IL-6 is thrombopoietin. Therefore, the purpose of this study was to compare the effects of TSF and IL-6 on percent 35S incorporation into platelets, platelet sizes, and the percentages of SAChE+ cells in C3H mice, and to determine if they produce the same or different responses. The results showed that two or four injections of a partially purified TSF (total dose of 2 or 4 units (U) over a 1- or 2-day period) increased percent 35S incorporation into platelets (P less than .005) and platelet sizes (P less than .005) of both normal and rebound-thrombocytotic mice when compared with values from other mice treated with human serum albumin, the carrier protein for both TSF and IL-6. In eight separate experiments, it was shown that IL-6 (40,000 U, 4 micrograms), when given to rebound-thrombocytotic mice in four injections over a 2-day period, produced a small but significant (P less than .005) increase in percent 35S incorporation into platelets. Additional studies showed that negative results were obtained when similar high doses of IL-6 were administered in two doses over a 1-day period. TSF, but not IL-6, stimulated an increase in platelet sizes of normal mice (P less than .005 to 0.0005); however, IL-6 increased platelet sizes of rebound-thrombocytotic mice when given in two of four injections (P less than .05 to .0005). Also, IL-6, but not TSF, caused anemia in normal mice (P less than .0005) that were given two injections and tested 3 days later. TSF stimulated an increase (P less than .005) in the percentage of SA-ChE+ cells; whereas IL-6, even at high doses, did not. Because of the observed differences in biologic responses of these two cytokines, we conclude that TSF and IL-6 are separate entities.
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PMID:Comparative effects of thrombopoietin and interleukin-6 on murine megakaryocytopoiesis and platelet production. 199 16

Megakaryocytopoiesis is a complex, highly regulated cellular and biologic process which leads to the production of platelets. The proliferation of megakaryocyte (MK) progenitors is mainly regulated by interleukin-3, granulocyte-macrophage colony-stimulating factor and an as yet uncharacterized MK colony-stimulating factor. The maturation of MKs to produce platelets is essentially regulated by interleukin-6 and thrombopoietin. Optimal megakaryocytopoiesis is controlled by appropriate combinations of positive and negative influence. Megakaryocytopoietic inhibition is controlled by transforming growth factor beta, platelet factor 4 and its related proteins, interferon-alpha and -gamma.
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PMID:Regulation of human megakaryocytopoiesis. 210 71

The range of known purified and cloned growth factors and their target cells within the megakaryocytic lineage is described. Data are reviewed outlining that megakaryocytopoiesis appears to be controlled at two levels: (i) by feedback control via circulating factors, and (ii) by factors within the marrow itself. Hypotheses are presented about the nature of thrombopoietin, its relationship to known growth factors, especially Interleukin-6 (IL-6), and the specificity of a thrombopoietic response following change in the circulating platelet mass.
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PMID:Stimulators of megakaryocyte development and platelet production. 210 74

Thrombopoietin (TPO), a regulatory factor in platelet production, was purified from the conditioned medium of TNK-01 cells cultured in the presence of human interleukin-1. The N-terminal sequence of purified TPO was determined to be VPPGEDSKDVAAPHRQPLT, identical to that of the N-terminal region of human interleukin-6 (IL-6). Two forms of TPO with molecular masses of 24 and 27 kDa were identified as IL-6 by Western analysis using an anti-IL-6 antibody. Commercial recombinant human IL-6 produced in Escherichia coli, stimulated megakaryocyte colony formation in the presence of mouse interleukin-3 and increased the number of peripheral platelets in mice in a dose-dependent manner. From these results, it is concluded that human IL-6 has thrombopoietic activity.
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PMID:Thrombopoietic activity of human interleukin-6. 229 97

To determine the biologic activity of interleukin-6 (IL-6) on megakaryocytopoiesis and thrombocytopoiesis in vivo, the cytokine was administered intraperitoneally to mice every 12 hours at varying doses for five days or for varying time intervals, based on the kinetic analysis of IL-6 serum levels indicating the peak of 40 minutes following injection, with no detection at 150 minutes. A dose-response experiment showed that IL-6 increased platelet counts in a dose-dependent fashion at a plateau stimulation level of 5 micrograms. Administration of 5 micrograms of IL-6 reproducibly elevated platelet counts at five days by approximately 50% to 60% of increase. Moreover, a striking increase in megakaryocytic size in response to IL-6 was elicited by the treatment, but no change in megakaryocyte numbers; whereas IL-6 administration did not expand CFU-MK numbers. The in vivo studies in this manner had negligible effects on other hematologic parameters, with the minor exception of monocyte levels. These data show that IL-6 acts on maturational stages in megakaryocytopoiesis and promotes platelet production in vivo in mice, suggesting that IL-6 functions as thrombopoietin.
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PMID:Interleukin-6 is a potent thrombopoietic factor in vivo in mice. 278 64

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


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