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)

Congenital thrombocytopenia with absent radii (TAR syndrome) is characterized by defective thrombopoiesis and bleeding in early infancy. To determine the frequency and responsiveness to cytokines of megakaryocyte progenitors (CFU-Meg) in TAR syndrome, the authors studied marrow samples from 3 patients and 6 normal controls, using optimally standardized megakaryocyte growth media incorporating interleukin-3, interleukin-6, stem cell factor, and granulocyte-monocyte colony-stimulating factor, with and without pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). CFU-Meg was identified with a specific staining system utilizing monoclonal antibodies to glycoprotein IIb/IIIa. Growth of small CFU-Meg colonies (3-20 cells/colony) was observed in all patients in cultures without PEG-rHuMGDF, with a mean frequency of 8 (range 5-12) per 2.25 x 10(5) mononuclear cells plated (control mean 23; range 2-70). Identical cultures of marrow cells from patients and controls with added PEG-rHuMGDF produced more colonies per dish (mean 17, range 8-23; control mean 30, range 6-62). Except for 1 case, however, patients' colonies in response to PEG-rHuMGDF remained smaller than those of controls. Two patients tested had higher plasma thrombopoietin levels than 6 normal subjects. The findings demonstrate proliferative and PEG-rHuMGDF-responsive megakaryocytic progenitors in TAR syndrome. The modest reduction in frequency of megakaryocyte progenitors and the suboptimal size of colonies in response to PEG-rHuMGDF are compatible with the reported defective signal transduction in the c-mpl pathway in TAR syndrome.
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PMID:Thrombocytopenia with absent radii: frequency of marrow megakaryocyte progenitors, proliferative characteristics, and megakaryocyte growth and development factor responsiveness. 1103 26

We investigated the effects of recombinant human thrombopoietin (TPO) in combination with various cytokines including erythropoietin (EPO), interleukin-3 (IL-3), interleukin-6 (IL-6), and stem cell factor (SCF) on megakaryopoiesis, and the expansion of CD34+CD41a+ cells from human cord blood CD34+ cells with these cytokines under serum-free conditions. Human cord blood CD34+ cells were cultured in Megacult (Stem Cell Technologies Inc. Vancouver, Canada) in the presence of recombinant growth factors. Colony-forming unit-megakaryocyte (CFU-M) colonies were counted on day 14. CD34+CD41a+ and CD34-CD41a+ cell expansion was analyzed using a serum-free liquid culture system for 7 days with recombinant growth factors. TPO alone had a concentration-dependent effect on megakaryocyte colony growth. At concentrations above 1 ng/ml, TPO supported significant CFU-Meg colony formation in a concentration-dependent manner. The combination of TPO plus other cytokines, including EPO, IL-3, and SCF, resulted in a synergistic enhancement of the number of CFU-Meg colonies, but IL-6 failed to enhance the effect of TPO. The number of CD41a+ cells increased after 7 days in liquid culture of human cord blood CD34+ cells with various cytokines (EPO, IL-3, IL-6, SCF) combined with TPO, but SCF plus TPO only resulted in a significant synergistic increment of CD34+CD41a+ cells compared with TPO alone. The results of the present study indicate that EPO, IL-3, and SCF can be synergistic with TPO to stimulate proliferation of CFU-Meg and suggest that SCF plus TPO can expand CD34+CD41a+ cells to effect the rapid recovery of platelets in patients following stem cell transplantation.
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PMID:Thrombopoietin is synergistic with other cytokines for expansion of cord blood progenitor cells. 1098 44

Paclitaxel and carboplatin chemotherapy is reported to be a platelet-sparing drug combination. This study investigated potential mechanisms for this observation by studying the effects of paclitaxel and carboplatin on (1) normal donor and chemotherapy patient-derived erythroid (burst-forming units-erythroid [BFU-E]), myeloid (colony-forming units-granulocyte/macrophage [CFU-GM]), and megakaryocyte (CFU-Meg) progenitor cell growth; (2) P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) messenger RNA (mRNA) expression; (3) serum thrombopoietin (Tpo), stem cell factor (SCF), interleukin-6 (IL-6), IL-11, IL-1beta, IL-8, and tumor necrosis factor-alpha levels in patients treated with paclitaxel and carboplatin; and (4) stromal cell production of Tpo and SCF after paclitaxel and carboplatin exposure. CFU-Meg were more resistant to paclitaxel alone, or in combination with carboplatin, than CFU-GM and BFU-E. Although all progenitors expressed P-gp protein and GST mRNA, verapamil treatment significantly, and selectively, increased the toxicity of paclitaxel and carboplatin to CFU-Meg, suggesting an important role for P-gp in megakaryocyte drug resistance. Compared to normal controls, serum Tpo levels in patients receiving paclitaxel and carboplatin were significantly elevated 5 hours after infusion and remained elevated at day 7 (287% +/- 63% increase, P <.001). Marrow stroma was shown to be the likely source of this Tpo. It is concluded here that P-gp-mediated efflux of paclitaxel, and perhaps GST-mediated detoxification of carboplatin, results in relative sparing of CFU-Meg, which may then respond to locally high levels of stromal cell-derived Tpo. The confluence of these events might lead to the platelet-sparing phenomenon observed in patients treated with paclitaxel and carboplatin chemotherapy.
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PMID:Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy. 1115 79

When people are exposed to large doses of ionizing rays in a short time, hematopoiesis is impaired and hemorrhage is one of the major clinical features. Suddenly decreasing platelet counts are responsible for the life-threatening hemorrhagic complication. Therefore, some cytokines have been used to improve thrombocytopoiesis in various radiation-induced thrombocytopenia models. Current measures for this purpose involve repeated intravenous or subcutaneous injections of recombinant proteins, which are expensive and inconvenient, or gene therapy with viral vectors that could not obviate the risk of infection. We tried to determine the possibility of gene therapy with plasmid vectors for radiation-induced hematopoietic injury, which could overcome the above-mentioned problem. In this study, we describe the enhanced efficiency of radiation on gene transfer with plasmid vector in vivo and the physiological role of expressed human interleukin-6 (hIL-6) in vivo on a radiation-induced thrombocytopenia model. After a single intramuscular injection of plasmid hIL-6 DNA on 6.5-Gy-irradiated mice, the hIL-6 protein level in mouse plasma was determined with enzyme-linked immunosorbent assay (ELISA). The level of hIL-6 began to increase from the 4th day, reached the peak value on about the 11th day, and remained at a higher level on the 28th day. Meanwhile, unirradiated mice injected with the same amount of plasmid DNA showed less hIL-6 on the 11th day after administration. Further experiments demonstrated that the hIL-6 level in 7.5-Gy-irradiated mice was about three times higher than that of 5.0-Gy-irradiated mice, suggesting radiation could improve gene transfer efficiency of plasmid DNA in vivo and might be dependent on radiation doses. The expression of hIL-6 in vivo showed a significant effect on hematopoietic recovery after radiation. Not only the platelet nadir in peripheral blood, but also the number of colony-forming cells in bone marrow rose. The increased platelet counts were partially due to the increase of reticulated platelet that reflected the activity of a given population of megakaryocyte in bone marrow. We conclude that radiation could significantly enhance the gene transfer efficiency of plasmid DNA and that gene therapy with plasmid vectors for radiation-induced hematopoietic injury might be more effective than other diseases without DNA repair.
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PMID:Administration of plasmid DNA expressing human interleukin-6 significantly improves thrombocytopoiesis in irradiated mice. 1173 66

The circulating angiogenic factors vascular endothelial growth factor-A, interleukin-6 and the fibrin D-dimer fragment were measured in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma. In addition, immunohistochemistry for vascular endothelial growth factor-A and interleukin-6 was performed on colorectal tumours of such patients. Serum and plasma vascular endothelial growth factor-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of vascular endothelial growth factor-A. Serum vascular endothelial growth factor-A is therefore not all tumour-derived. In contrast, serum interleukin-6 was highly elevated in the draining veins in agreement with expression of interleukin-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of vascular endothelial growth factor-A was found to be regulated by interleukin-6. Thus, the higher platelet vascular endothelial growth factor-A load resulting in higher serum vascular endothelial growth factor levels in cancer patients may partly result from an interleukin-6 mediated up-regulation of the expression of vascular endothelial growth factor-A in the precursor of the platelet, i.e. the megakaryocyte. We also confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that interleukin-6 indirectly promotes tumour angiogenesis through its up-regulation of the vascular endothelial growth factor-A load in platelets. In addition, the correlations found between peripheral venous interleukin-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for interleukin-6 in extra-vascular fibrinogen metabolism. Our results suggest a pivotal role for interleukin-6 in the intrinsic link between haemostasis and angiogenesis. This might be of importance in the development of anti-angiogenic agents based on interference with haemostasis.
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PMID:Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer. 1245 74

Stromal cell-derived factor-1 (SDF-1/CXCL12) enhances survival of myeloid progenitor cells. The two main questions addressed by us were whether these effects on the progenitors were direct-acting and if SDF-1/CXCL12 enhanced engrafting capability of competitive, repopulating mouse stem cells subjected to short-term ex vivo culture with other growth factors. SDF-1/CXCL12 had survival-enhancing/antiapoptosis effects on human bone marrow (BM) and cord blood (CB) and mouse BM colony-forming units (CFU)-granulocyte macrophage, burst-forming units-erythroid, and CFU-granulocyte-erythroid-macrophage-megakaryocyte with similar dose responses. The survival effects were direct-acting, as assessed on colony formation by single isolated human BM and CB CD34(+++) cells. Effects were mediated through CXCR4 and G(alpha)i proteins. Moreover, SDF-1/CXCL12 greatly enhanced the engrafting capability of mouse long-term, marrow-competitive, repopulating stem cells cultured ex vivo with interleukin-6 and steel factor for 48 h. These results extend information on the survival effects mediated through the SDF-1/CXCL12-CXCR4 axis and may be of relevance for ex vivo expansion and gene-transduction procedures.
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PMID:Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells. 1271 78

Thrombocytopenia remains a significant clinical problem for which only symptomatic therapy, namely platelet transfusion, is available for management of acute events. Platelet transfusions are often complicated by febrile reactions, as well as the risk of transmission of infectious agents and the likelihood of alloimmunization, which then decreases the effectiveness of additional transfusion support. The availability of a hematopoietic cytokine that could reliably stimulate platelet recovery, analogous to the effect of granulocyte colony-stimulating factor on neutrophil recovery following chemotherapy, would greatly enhance supportive care in cancer and provide an effective therapy for a variety of diseases that cause thrombocytopenia. To identify such a thrombopoietic cytokine, studies initially focused on regulatory molecules that stimulates early multipotent hematopoietic progenitors, such as interleukin-1 and interleukin-6. Unfortunately, these cytokines had poor efficacy and significant toxicity in human testing. Recombinant human interleukin-11, an early-acting cytokine, has modest efficacy and clinically challenging toxicities, but in the absence of other active drugs, it has been licensed for prevention of severe chemotherapy-induced thrombocytopenia. Recent interest has focused on analogs of thrombopoietin, the endogenous regulator of thrombopoiesis, which have the potential for much greater efficacy with minimal toxicity due to the more specific targeting of megakaryocyte-specific signaling.
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PMID:Challenges in the development of platelet growth factors: low expectations for low counts. 1290 Nov 32

Thrombopoietin (TPO) plays a pivotal role in megakaryopoiesis. TPO initiates its biological effects by binding to its receptor Mpl. A recombinant protein consisting of a carrier Fc domain linked to multiple Mpl-binding domains was constructed, and is called AMG531. To define the biological activity of AMG531, we examined the ability of AMG531 to support CFU-Meg growth and to promote megakaryocyte maturation in vitro. AMG531 stimulates CFU-Meg growth in a dose-dependent manner, and acts in concert with erythropoietin, stem cell factor, interleukin-3, and interleukin-6 to enhance CFU-Meg growth, similar to parallel experiments with TPO. AMG531-stimulated serum-free liquid cultures support the development of mature polyploid megakaryocytes with a predominant DNA content of 32 N and 64 N, identical to that of parallel TPO-stimulated cultures. Competitive binding experiments show that AMG531 effectively competes with 125I-TPO for binding to BaF3-Mpl cells or normal platelets. Treatment of BaF3-Mpl cells with AMG531 or with TPO resulted in rapid tyrosine phosphorylation of Mpl, JAK2, and STAT5. These results indicate that AMG531 is a potent stimulant of megakarypoiesis in vitro, and provide support for its further characterization in vivo.
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PMID:AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. 1469 60

The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
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PMID:Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. 1470 36

Human megakaryocyte differentiation and maturation were studied in fresh marrow aspirates by using multiparameter flow cytometric correlative analysis. The expression of glycoprotein (GP)IIb/IIIa, GPIIIa, GPIb, and CD36 correlated directly with cell size and ploidy (r > 0.97); however, GPIb acquisition was relatively slow. von Willebrand factor (VWF) is robustly expressed by early (2N and 4N) megakaryocytes, enabling their complete resolution from the other marrow cells at a level superior to that achieved with GPIIb/IIIa. Expression of myeloid CD45 and immunoglobulin G (IgG)-FcgammaRII receptor (CDw32) increased with megakaryocyte maturation and contrasted with the declining expression of HLA-DR (negative in platelets). Interleukin-6 receptor expression in megakaryocytes was higher than in other marrow cells. By using the time-of-flight technique, the diameter of the megakaryocyte population was 37 +/- 4 microm (mean +/- 1 SD) compared with 14 +/- 2 microm for the total marrow cells, ranging from 21 +/- 4 microm for 2N cells to 56 +/- 8 microm for 64N cells. Cell size directly correlated with cell DNA (r = 0.98). Receptor density of GPIIb/IIIa and GPIb decreased with the transition from 2N to 4N cells, then reached maximum at 32N cells. In conclusion, the present methods are useful for studying in vivo human megakaryocytopoiesis in normal and altered states. The expression of VWF is a sensitive and distinctive marker for the identification of young marrow megakaryocytes.
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PMID:Human marrow megakaryocyte differentiation: multiparameter correlative analysis identifies von Willebrand factor as a sensitive and distinctive marker for early (2N and 4N) megakaryocytes. 1519 50


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