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)

Eighteen advanced cancer patients received weekday subcutaneous injections of recombinant interleukin-6 (rIL-6) for 4 weeks at escalating doses. Patients were evaluated for hematologic and immune system effects. Hematologic monitoring included WBC, differential, Hgb and Hct, platelet counts, and assessment of marrow and peripheral blood progenitors. Immunologic monitoring included evaluation of acute-phase reactants (APRs), immunophenotyping, serum cytokine levels, cytokine-induced proteins, and cytokine messenger RNA (mRNA). The maximal tolerated dose (MTD) was 8.0 micrograms/kg/day, with neurocortical toxicity as the major limiting factor. All patients became anemic, and most had fever and chills. APRs were increased throughout treatment. WBCs increased transiently on day 2; granulocytes and monocytes increased again through day 26, whereas lymphocytes decreased to baseline or lower levels. Platelets responded by day 12 and increased through day 26 at the MTD with no effect on colony-forming unit-megakaryocyte (CFU-Mk). Peripheral WBC and RBC progenitors were not affected but decreased in the marrow. T-cell percentages declined with little effect on absolute numbers; T-cell activation was seen. CD45RO+ T cells decreased, but there was no significant effect on CD8+ CD28+ T cells. Neither B cells nor natural killer (NK) cells were affected. However, evidence of monocyte effects included upregulation of CD71, induction of the cytokine-induced proteins 2-5A synthetase and neopterin, and increases in tumor necrosis factor-alpha (TNF-alpha) mRNA. Serum cytokines were undetected, and mRNA for IL-1 beta, IL-2, and interferon-gamma (IFN-gamma) was not induced; however, mRNA for IL-4 and IL-10 did increase suggesting activation of Th2-like T cells. One mixed tumor response was seen. We conclude that IL-6 alone has systemic activity on the immune system, as well as the hematopoietic system, which at the MTD, primarily involves induction of APR, activation and expansion of monocytes, and activation of Th2-like T cells.
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PMID:Hematologic and immunologic evaluation of recombinant human interleukin-6 in patients with advanced malignant disease: evidence for monocyte activation. 881 98

Prolonged thrombocytopenia is a frequent clinical problem in cancer patients undergoing high-dose chemotherapy and autologous transplantation. The use of GM-CSF as an adjuvant to autologous bone marrow transplantation (ABMT) has significantly reduced the duration of neutropenia after high-dose chemotherapy but failed to accelerate platelet recovery in transplanted patients. The more rapid hematopoietic reconstitution obtained by autologous mobilized peripheral blood progenitor cell transplantation (PBPCT) after high-dose chemotherapy has resulted in its increasing use instead of ABMT. However, PBPCT does not always produce faster platelet engraftment after high-dose chemotherapy, and persistent thrombocytopenia remains a significant clinical problem in PBPC-transplanted patients. The duration of severe thrombocytopenia (requiring frequent platelet transfusions) until platelet recovery varies widely depending on the quality of the autograft and previous radiotherapy or chemotherapy. The median days to reach 20,000/microliters platelets ranged from 10 to 32 days. Pilot clinical studies in which cancer patients were transplanted with enriched CD34+ cell autografts, obtained from G-CSF-mobilized PB, showed a similar platelet recovery after high-dose chemotherapy but also wide variation among the patients. The median days to reach 20,000/microliters platelets ranged from 9 to 38 days. The dose of CFU-GM in the autograft has been identified as the best predictive factor for hematopoietic recovery (p < 0.0001) after high-dose chemotherapy and autologous PBPCT in 118 patients with hematologic malignancies. A similar assessment of the megakaryocyte progenitor cells (BFU-MK and CFU-MK) in the autograft not only could predict time to platelet recovery but also could help to optimize the number and method of mobilization of the PBPC required to shorten the problematic obligatory 2-week duration of thrombocytopenia after high-dose chemotherapy. A routine assessment of the number of BFU-MK and CFU-MK present in each autograft and correlation with platelet recovery after transplantation would enable us to define the clinical threshold cell dose required for rapid platelet recovery. Recently, several non-specific cytokines with thrombopoietic activity have been evaluated in phase I clinical trials, including interleukin-1, interleukin-3 followed by GM-CSF, interleukin-6, and interleukin-11 in cancer patients, showing an encouraging trend toward a decrease in thrombocytopenia after chemotherapy. The recently cloned specific platelet cytokine, thrombopoietin, is currently undergoing phase I clinical studies, and the results are awaited with interest.
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PMID:Thrombocytopenia after high-dose chemotherapy and autologous stem cell transplantation: an unresolved problem and possible approaches to resolve it. 887 16

The regulation of megakaryocytopoiesis and thrombopoiesis appears to be under the control of an array of hematopoietic growth factors. To determine the relationship of endogenous thrombopoietic cytokine levels and circulating platelet (PLT) counts, we measured the levels of thrombo-poietin (TPO), interleukin-11 (IL-11), and interleukin-6 (IL-6) in patients with significant thrombocytopenia secondary to both marrow hypoplasia and increased PLT destruction. Increased endogenous levels of TPO and IL-11, but not IL-6, were detected in bone marrow transplant patients with thrombocytopenia following myeloablative therapy (BMT/MAT) (TPO: 1,455.5 +/- 87.3 pg/mL, [PLT 39,600 +/- 7,800/microL], P < .001, n = 12; IL-11: 227.9 +/- 35 pg/mL, [PLT 32,900 +/- 57,000/microL], P < .05, n = 19; IL-6: 25.8 +/- 8.4 pg/mL, [PLT 32,800 +/- 5,057/microL], P > .05, n = 4] v normal donors [TPO < 150 pg/mL, n = 8; IL-11 < 50 pg/mL, n = 9; IL-6 < 10 pg/mL, n = 5 [PLT 203,000 +/- 7,500/microL]. There was a significant inverse correlation between endogenous levels of TPO and IL-11, but not IL-6, and PLT counts in the MAT/BMT patients (TPO: r = -0.57, P < .0001, n = 188; IL-11: r = -0.329, P < .0001, n = 249; IL-6: r = -0.1147, P > .05, n = 62). In patients with immune thrombocytopenia purpura (ITP), with decreased PLT survival, but intact bone marrow megakaryocytopoiesis, endogenous IL-11 levels were significantly increased (328.0 +/- 92.6 pg/mL, [PLT: 20,900 +/- 3,000/microL], P < .05, n = 25). However, endogenous TPO levels remained undetectable (< 150 pg/mL, [PLT 30,500 +/- 5,500/microL], n = 15). These results suggest that there may be differential mechanisms regulating endogenous TPO, IL-11, and IL-6 levels during acute thrombocytopenia and suggest that the absolute number of circulating PLTs may not always be the sole regulator of endogenous TPO levels. Other mpl-expressing cells of the megakaryocyte lineage may contribute to the regulation of circulating TPO levels as well. Our results also suggest IL-11 levels may in part, be regulated by a negative feedback loop based on circulating PLT counts, but also may, in part, be regulated by a variety of inflammatory agonists. Both TPO and IL-11, therefore, appear to be active thrombopoietic cytokines regulating, in part, megakaryocytopoiesis during states of acute thrombocytopenia.
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PMID:Differential mechanisms in the regulation of endogenous levels of thrombopoietin and interleukin-11 during thrombocytopenia: insight into the regulation of platelet production. 889

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

Platelet numbers and circulating haemopoietic progenitor cells were examined in 12 patients with advanced malignancies who were receiving recombinant human interleukin-6 (rhIL-6) as part of an investigation of its thrombopoietic effects. Patients received recombinant glycosylated IL-6 by daily subcutaneous injection for 7 consecutive days in doses of 1, 3 or 10 micrograms/kg/day. Platelet numbers increased reaching a peak on days 12-15 with a mean on day 15 of 198.1% of pre-treatment values. This was accompanied by a significant fall in the mean platelet volume (mean decrease of 10.6%, P = 0.0044). No significant correlation was seen between the IL-6 dose and the change in platelet number. No significant differences were observed between pre- and post-treatment levels of circulating erythroid burst-forming units (E-BFU) and granulocyte macrophage colony-forming units (GM-CFU) but a small significant increase was seen in circulating primitive progenitor cells measured in a plastic-adherent (P delta) assay (P = 0.025). As positive controls, a group of patients treated with cyclophosphamide/G-CSF showed significant increases in GM-CFU (P = 0.018), E-BFU (P = 0.018) and P delta progenitors (P = 0.028). These data suggest that the thrombopoietic effects of IL-6 are mediated at a relatively late stage via effects on megakaryocyte differentiation, with a relatively small effect on circulating haemopoietic progenitors.
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PMID:Effects of interleukin 6 administration on platelets and haemopoietic progenitor cells in peripheral blood. 893 83

Interleukin-6 (IL-6) is a cytokine with pleiotropic biologic activities on B cells, T cells, and hematopoietic progenitors. The present study was undertaken to assess pharmacodynamic effects of subcutaneous administration of IL-6 on blood counts, immunologic parameters, and acute-phase reactants. Blood samples were taken from patients with advanced renal cell cancer participating in a phase II trial of recombinant human IL-6. Multiparameter FACS analyses of peripheral blood mononuclear cells were performed using antibodies against CD3, CD4, CD8, HLA-DR, CD56, CD28, CD38, CD19, sIgM, and sIgG. Serum levels of IL-10, soluble CD23 (sCD23), sCD25, IL-1 receptor antagonist protein (IL-1RA), soluble tumor necrosis factor (TNF) receptors (sTNF-R) p55 and p75, and soluble IL-6 receptor (sIL-6R) were detected by ELISA systems. Levels of C-reactive protein (CRP), neopterin, fibrinogen, beta 2-microglobulin, and immunoglobulins M, G, and A were measured by standard methods. In response to administration of IL-6, a significant increment in platelet counts was observed, reaching peak levels after 21 days of treatment. In contrast, leukocyte subsets remained unaffected. No change in number of immunophenotype of peripheral blood B cells, T cells, or natural killer cells could be detected following IL-6 administration. Blood levels of sCD23, IL-10, sIL-6R, neopterin, beta 2-microglobulin, and immunoglobulin subsets were not influenced by cytokine therapy. However, administration of IL-6 led to a slow increment of acute-phase reactants CRP and fibrinogen. Furthermore, the anti-inflammatory molecules sTNF-R p55 and p75 were induced by IL-6, whereas serum levels of IL-1RA remained unchanged. Finally, an increase in blood levels of sCD25 was observed. In conclusion, IL-6 in vivo predominantly acts as a regulator of inflammation and a megakaryocyte differentiation factor.
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PMID:Immunomodulatory and hematopoietic effects of recombinant human interleukin-6 in patients with advanced renal cell cancer. 893 65

Formation of proplatelets from megakaryocytes is believed to be the first step of platelet production in vitro. In this study, we evaluated the effects of recombinant human thrombopoietin (hTPO) on the development of proplatelets from a GpIIb/IIIa+ population of rat bone marrow cells highly enriched for late megakaryocyte progenitors (GpIIb/IIIa+ CFU-MK) that we recently found to be a primary target population of TPO. Quantitative measurement of hTPO-induced proplatelet formation was performed in liquid cultures. Proplatelet formation from megakaryocytes derived from GpIIb/IIIa+ CFU-MK in the presence of hTPO began on day 4 of culture and peaked the following day. On day 5 of culture, lower concentrations of hTPO expanded the number of megakaryocytes, increased the number of proplatelets and the percentage of proplatelet-developing megakaryocytes. Increasing hTPO concentrations resulted in a modest decrease in proplatelet development. We next used hTPO to derive immature or mature megakaryocytes from GpIIb/IIIa+ CFU-MK. These populations of cultured megakaryocytes spontaneously formed proplatelets when recultured in the absence of exogenous hTPO. The addition of hTPO at higher concentrations modestly augmented proplatelet production from immature megakaryocytes derived from 2-day liquid cultures. However, either murine interleukin-6 (IL-6) or human IL-11, but not rat IL-3, was more potent than hTPO in augmenting proplatelet formation from immature megakaryocytes. Each of these four cytokines had an inhibitory effect on proplatelet formation from more differentiated megakaryocytes derived from 3-day liquid cultures. These results indicate that TPO enhances proplatelet production primarily by stimulating CFU-MK to increase the number of proplatelet-forming megakaryocytes and that its action is clearly different from those of other cytokines that also stimulate megakaryocytopoiesis.
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PMID:Action of thrombopoietin at the megakaryocyte progenitor level is critical for the subsequent proplatelet production. 901 17

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

Altered platelet morphology and function have been reported in patients with diabetes. They are likely to be associated with the pathological processes and increased risk of vascular disease seen in these patients. Mean platelet volume (MPV), platelet count, and megakaryocyte (MK) ploidy (DNA content) were measured in (1) nondiabetics with normal coronary arteries, (2) nondiabetics with coronary artery atherosclerosis, (3) diabetics without evidence of vascular complications, and (4) diabetics with vascular disease. The platelet count (+/- SD) was increased in all groups but only significantly in the diabetics with vascular disease (236 +/- 65 versus 250 +/- 54 versus 257 +/- 64 versus 295 +/- 90 [P < or = .05] x 10(9)/L, for groups, I, II, II, and IV, respectively). The MPV was significantly increased in patients with atherosclerosis (7.0 +/- 0.4 versus 8.0 +/- 1.2 [P < or = .05] versus 7.2 +/- 0.9 versus 8.1 +/- 0.9 [P < or = .05] IL). Geometric mean MK ploidy was significantly increased in all groups compared with controls (16 +/- 1.5 versus 18.7 +/- 1.8 [P < or = .05] versus 19.8 +/- 1.6 [P < or = .05] versus 20.1 +/- 2.7 [P < or = .05]). Furthermore, some patients with vascular disease and/or diabetes had a modal ploidy shift from 16 (the normal mammalian modal ploidy) to 32, with a concomitant reduction of MKs in the 8 and 16 ploidy classes. This shift was seen particularly in the diabetics with vascular disease (P = .007). Interleukin-6 (IL-6) levels were measured and were elevated in patients with atherosclerosis; the highest levels were found in the diabetic patients (0.7 +/- 0.9 versus 5.3 +/- 5.5 [P < or = .05] versus 2.5 +/- 2.8 versus 6.7 +/- 5.5 [P < or = .05] ng/L). In the diabetic patients with atherosclerosis, fibrinogen levels were also increased (2.85 +/- 0.76 versus 3.34 +/- 1.32 versus 2.43 +/- 1.50 versus 5.59 +/- 1.72 [P < or = .05] g/L). Furthermore, IL-6 levels correlated with MK ploidy (r = .45, P = .009) and fibrinogen levels (r = .5, P = .0001). This study demonstrates that patients with vascular disease, particularly diabetics, have an altered MK ploidy distribution, showing a shift toward higher ploidy in association with an increased platelet mass (count x volume). Changes in platelets in diabetes probably reflect MK changes, which themselves are a response to systemic change.
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PMID:Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. 910 97

The recombinant hemopoietic factors of megakaryocyte potentiator (MEG-POT) were studied to compare their activity in stimulating proplatelet process formation (PPF) with thrombopoietin (TPO, c-MpI ligand). For the assay, a highly enriched (> 95%) population of more than 90% viable megakaryocytes was isolated from rat bone marrow using the immunomagnetic beads method and cultured with fetal calf serum (FCS) or in a serum-free condition. Megakaryocytes developing slender beaded cytoplasmic processes (proplatelet processes) were observed on both inverted phase contract microscopy and scanning electron microscopy. A large number of proplatelet process clusters were dose-dependently formed with the addition of varying doses of recombinant erythropoietin (rEpo) and interleukin-6 (rIL-6) as well as TPO. Epo and IL-6 were demonstrated to act synergistically solely at low doses in the development of PPF (P < 0.05). Other recombinant factors such as IL-11, leukemia inhibitory factor (LIF) and erythroid differentiation factor (EDF) appeared weak or ineffective. From these in vitro observations, it was suggested that a synergism of Epo and IL-6 might play a significant role in the terminal stage of megakaryocyte maturation leading to platelet release.
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PMID:Synergistic effects of erythropoietin and interleukin-6 on the in vitro proplatelet process formation of rat megakaryocytes. 911 Mar 49


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