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)

We have evaluated the expression of growth factor receptors (GFRs) on early hematopoietic progenitor cells (HPCs) purified from human adult peripheral blood and induced in liquid suspension culture to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk), or monocytic (Mo) lineage. The receptors for basic fibroblast GF (bFGF), erythropoietin (Epo), thrombopoietin (Tpo), and macrophage colony-stimulating factor (MCSF) have been only assayed at mRNA level; the majority of GFRs have been evaluated by both mRNA and protein analyses: the expression patterns were consistent at both levels. In quiescent HPCs the receptors for early-acting [flt3 ligand (FL), c-kit ligand (KL), bFGF, interleukin-6 (IL-6)] and multilineage [IL-3, granulocyte-macrophage CSF (GM-CSF)] HGFs are expressed at significant levels but with different patterns, eg, kit and flt3 are detected on a majority and minority of HPCs, respectively, whereas IL-3Rs and GM-CSFRs are present on almost all HPCs. In the four differentiation pathways, expression of early-acting receptors shows a progressive decrease, more rapidly for bFGFR-1 and flt3 than for c-kit; furthermore, c-kit is more slowly downmodulated in the E and Mk than the G and Mo lineages. As a partial exception, IL-6Rs are still detected through the early or late stages of maturation in the Mk and Mo lineages, respectively. IL-3R expression is progressively and rapidly downmodulated in both E and Mk pathways, whereas it moderately decreases in the Mo lineage and is sustained in the G series. The expression of GM-CSFR is gradually downmodulated in all differentiation pathways, ie, the receptor density markedly decreases but late erythroblasts are still partially GM-CSFR+ and terminal G, Mk and Mo cells are essentially GM-CSFR+. Expression of receptors for late-acting cytokines is lineage-specific. Thus, EpoR, G-CSFR, TpoR, and M-CSFR exhibit a gradual induction followed by a sustained expression in the E, G, MK, and Mo lineages, respectively. In the other differentiation pathways the expression of these receptors is either absent or initially low and there-after suppressed. These observations are compatible with the following multi-step model. (1) The early-acting GFRs are expressed on quiescent HPCs with different patterns, whereas the multilineage GFRs are present on > or = 90% to 95% HPCs. (2) Multilineage GFs, potentiated by early-acting HGFs, trigger HPCs into cycling. HPC proliferation/differentiation is followed by declining expression of the early-acting GFRs and in part of multilineage GFRs (see above). (3) Multilineage GFs trigger the expression of the unilineage GFRs (see Testa U, et al: Blood 81:1442, 1993). Interaction of each unilineage GF with its receptor leads to sustained expression of the receptor (possibly via transcription factors activating the receptor promoter) and thus mediates differentiation/maturation through the pertinent lineage.
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PMID:Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors. 889 4

The Flk-2/flt3 ligand (FL) was evaluated and compared with c-kit ligand (KL) for its in vitro proliferative effects on CD34+ cells from human fetal liver, umbilical cord blood, bone marrow, and mobilized peripheral blood. Using a 7-day liquid culture system, FL in combination with interleukin-3 (IL-3), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF) was comparable with KL in combination with IL-3, IL-6, and G-CSF for the expansion of hematopoietic progenitors. When FL-containing cultures were assayed after 21 or 28 days, a greater number of progenitors were generated as compared with KL-containing cultures. Using bone marrow microvascular endothelial cells as support stroma, cultures supplemented with FL generated a greater number of progenitors in both the nonadherent and adherent layers at day 35. These data suggest that FL ligand, in combination with other cytokines, can be used for short-term ex vivo expansion of hematopoietic progenitors and facilitates the preservation and possible expansion of primitive cells capable of long-term generation of progenitors.
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PMID:The effects of Flk-2/flt3 ligand as compared with c-kit ligand on short-term and long-term proliferation of CD34+ hematopoietic progenitors elicited from human fetal liver, umbilical cord blood, bone marrow, and mobilized peripheral blood. 911 54

Umbilical cord blood has provides an alternative source to bone marrow for transplantation in children and some adults. However it has been thought to be necessary to expand hematopoietic stem cells in cord blood for adult-size transplantation. Flow-cytometric analysis revealed that most immature hematopoietic progenitors express gp130 but not interleukin-6 receptor (IL-6R). We established an ex vivo expansion system of human hematopoietic stem/progenitor cells using soluble IL-6R (sIL-6R). A combination of sIL-6R/IL-6 complex and SCF expanded CFU-Mix approximately 60-fold in both serum-containing and serum-free cultures by day 14. Addition of anti-gp130 mAbs and anti-IL-6R mAb to the above cultures dose-dependently inhibited the expansion of progenitors, suggesting that gp130 signalling initiated by the sIL-6R/IL-6 complex is important for significant expansion of human hematopoietic stem/progenitor cells. Addition of thrombopoetin and/or Flk2/Flt3 ligand (FL) to culture with sIL-6R/IL-6/SCF augmented the expansion of not only hematopoietic progenitors assayable in clonal culture but also hematopoietic stem cells estimated by NOD/SCID mice. Recent evidence shows that hematopoietic stem cells first occur and expand in aorta-gonad-mesonephros(AGM) region at 10 to 11 days post coitum(dpc) in murine, which suggests that AGM region at this stage provides a microenvironment suitable for development for hematopoietic stem cells. We reported here on a novel stromal cell line derived from the AGM region at day 10.5 dpc, which supported for 6 weeks generation of human multipotential hematopoietic progenitors from cord blood CD34+38- primitive hematopoietic cells in a co-culture system. This cell line is expected to elucidate molecular mechanisms regulating early hematopoiesis, and pave the way for developing strategies for ex vivo expansion of human transplantable hematopoietic stem cells.
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PMID:[Cord blood transplantation and ex vivo expansion of hematopoietic stem cells]. 1047 32

The development of culture systems that facilitate ex vivo maintenance and expansion of transplantable hematopoietic stem cells (HSCs) is vital to stem cell research. Establishment of such culture systems will have significant impact on ex vivo manipulation and expansion of transplantable stem cells in clinical applications such as gene therapy, tumor cell purging, and stem cell transplantation. We have recently developed a stromal-based culture system that facilitates ex vivo expansion of transplantable human HSCs. In this stromal-based culture system, 2 major contributors to the ex vivo stem cell expansion are the addition of leukemia inhibitory factor (LIF) and the AC6.21 stromal cells. Because the action of LIF is indirect and mediated by stromal cells, we hypothesized that LIF binds to the LIF receptor on AC6.21 stromal cells, leading to up-regulated production of stem cell expansion promoting factor (SCEPF) and/or down-regulated production of stem cell expansion inhibitory factor (SCEIF). Here we demonstrate a secreted SCEPF activity in the conditioned media of LIF-treated AC6.21 stromal cell cultures (SCM-LIF). The magnitude of ex vivo stem cell expansion depends on the concentration of the secreted SCEPF activity in the SCM-LIF. Furthermore, we have ruled out the contribution of 6 known early-acting cytokines, including interleukin-3, interleukin-6, granulocyte macrophage colony-stimulating factor, stem cell factor, flt3 ligand, and thrombopoietin, to this SCEPF activity. Although further studies are required to characterize this secreted SCEPF activity and to determine whether this secreted SCEPF activity is mediated by a single factor or by multiple growth factors, our results demonstrate that stromal cells are not required for this secreted SCEPF activity to facilitate ex vivo stem cell expansion. (Blood. 2000;95:1957-1966)
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PMID:A secreted and LIF-mediated stromal cell-derived activity that promotes ex vivo expansion of human hematopoietic stem cells. 1096 Feb 42

Expansion of haemopoietic stem cells from placental blood has been obtained with a combination of flt3 ligand (FL), thrombopoietin (TPO), kit-ligand (KL) with or without interleukin-6 (IL6) in serum-replete medium. For clinical use, cell expansion in the absence of serum is a clear advantage. Therefore, stem cell expansion in serum-free (SF) medium with a combination of three (FL, TPO, KL) or four (FL, TPO, KL, IL6) growth factors was compared with the results obtained using fetal calf serum (FCS) or human serum (HS). Human CD34(+) placental blood cells were cultured in the presence of FL, TPO, KL +/- IL6 with SF medium, HS and FCS for up to 8 weeks. CD34(+), CFC, LTC-IC content was measured at intervals. To determine the in vivo repopulating capacity of expanded cells, CD34(+) expanded cells were transplanted in sublethally irradiated NOD/SCID mice. With the three growth factor combination the CD34(+) cell number increased steadily up to the 8 weeks of culture. CD34(+) cells were expanded 67.5-fold with SF, 11.7 with HS and 49.2 with FCS. However, when CFCs and LTC-ICs were considered, a continuous expansion was observed only with HS and FCS, whereas in SF medium after 6 weeks their number started to decline. The addition of IL-6 did not change the expansion significantly. Cells grown ex vivo for 14 days were transplanted into NOD/SCID mice. The engraftment of human cells in mice was higher for serum-replete than for SF expanded cells. Nevertheless, SF cultured cells were also able to engraft both marrow and spleen in all animals. In addition, engrafted human cells still maintained clonogenic ability. With KL, FL, TPO +/- IL6 it is possible to expand haemopoietic progenitor cells in a SF medium. Compared with serum-replete cultures, the absolute number of clonogenic cells and in vivo repopulating cells is lower. Although the degree of expansion remains significant, a clinical trial still needs to be carried out to address the question of whether this expansion might be useful in reducing post-transplant aplasia.
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PMID:Role of different medium and growth factors on placental blood stem cell expansion: an in vitro and in vivo study. 1191 35

Ex vivo proliferation of hematopoietic stem cells (HSCs) is important for cellular and gene therapy but is limited by the observation that HSCs do not engraft as they transit S/G(2)/M. Recently identified candidate inhibitors of human HSC cycling are transforming growth factor-beta(1) (TGF-beta(1)) and stroma-derived factor-1 (SDF-1). To determine the ability of these factors to alter the transplantability of human HSCs proliferating in vitro, lin(-) cord blood cells were first cultured for 96 hours in serum-free medium containing Flt3 ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These cells were then transferred to medium containing Steel factor and thrombopoietin with or without SDF-1 and/or TGF-beta(1) for 48 hours. Exposure to SDF-1 but not TGF-beta(1) significantly increased (> 2-fold) the recovery of HSCs able to repopulate nonobese diabetic/severe combined immunodeficiency mice. These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo.
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PMID:Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID mice. 1196 17

Evidence is provided that dendritic cells (DC) generated by either long-term bone marrow cell (BMC) culture with Flt3L and interleukin-6 (IL-6), or after short-term BMC culture with granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), contain heterogeneous cell populations of admixed DC and Mphi, regardless of the cytokine source. By employing GM-CSF-independent culture systems with the aid of Flt3/Flk-2 ligand and IL-6 and phenotypic characterization of BMC-derived DC and skin Langerhans cells (LC), revealed similar phenotypes. Furthermore, CD103 (OX62), which is widely used for rat DC separation, was found to be insufficient to enrich DC, due to downregulation of the marker. In this regard, the most efficient selection of rat DC, was obtained by CD161a (NKR-P1A), a member of the C-type lectin family. Despite the phenotypic similarity with BMC-derived DC, the nucleus of LC showed a distinct morphology. A large population of DC generated by Flt3L/IL-6 from GM-CSF receptor-deficient mice by do not express NK1.1 (NKR-P1B and NKR-P1C). The profiles for BMC-derived DC were the same as for skin Langerhans cells.
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PMID:Phenotype and functional identity of GM-CSF-independent dendritic cells generated by long-term propagation of DC progenitor cells in bone marrow cells and skin Langerhans cells. 1580 32

RNA molecules such as single-stranded RNA (ssRNA) and small interfering RNA (siRNA) duplexes induce Toll-like receptor (TLR)-mediated immune stimulation after intracellular delivery. We have previously shown that selective incorporation of 2'-O-methyl (2'OMe) residues into siRNA abrogates cytokine production without reduction of gene silencing activity. Here we show that 2'OMe-modified RNA acts as a potent inhibitor of RNA-mediated cytokine induction in both human and murine systems. This activity does not require the direct incorporation of 2'OMe nucleotides into the immunostimulatory RNA or that the 2'OMe nucleotide-containing RNA be annealed as a complementary strand to form a duplex. Our results indicate that 2'OMe RNA acts as a potent antagonist of immunostimulatory RNA. We further show that 2'OMe RNA is able significantly to reduce both interferon-alpha (IFN-alpha) and interleukin-6 (IL-6) induction by the small-molecule TLR7 agonist loxoribine in human peripheral blood mononuclear cells (human PBMCs), in murine Flt3L dendritic cells (Flt3L DCs), and in vivo in mice. These results indicate that 2'OMe-modified RNA may have utility as an inhibitor of TLR7 with potential applications in the treatment of inflammatory and autoimmune diseases that involve TLR7-mediated immune stimulation.
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PMID:2'-O-methyl-modified RNAs act as TLR7 antagonists. 1757 74

Conditions that influence the selective development or recruitment of connective tissue-type and mucosal-type mast cells (MCs) are not well understood. Here, we report that cynomolgus monkey embryonic stem (ES) cells cocultured with the murine aorta-gonad-mesonephros-derived stromal cell line AGM-S1 differentiated into cobblestone (CS)-like cells by day 10-15. When replated onto fresh AGM-S1 with the addition of stem cell factor, interleukin-6, and Flt3 ligand, these CS-like cells displayed robust growth and generated almost 100% tryptase/chymase double-positive MCs within 3 weeks. At all time points, the percentage of tryptase-positive cells did not exceed that of chymase-positive cells. These ES-derived MCs were CD45+/Kit+/CD31+/CD203c+/HLA-DR- and coexpressed a high-affinity IgE receptor on their surface, which was upregulated after IgE exposure. Electron microscopy showed that they contained many electron dense granules. Moreover, ES-derived MCs responded to stimulation by via IgE and substance P by releasing histamine. These results indicate that ES-derived MCs have the phenotype of functionally mature connective tissue-type MCs. The rapid maturation of ES-derived MCs suggests a unique embryonic pathway in primates for early development of connective tissue-type MCs, which may be independent from the developmental pathway of mucosal-type MCs.
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PMID:Direct development of functionally mature tryptase/chymase double-positive connective tissue-type mast cells from primate embryonic stem cells. 1799 16

Circulating myeloid cells such as plasmacytoid dendritic cells (pDC), blood DC and monocytes act as blood sentinels detecting invading pathogens through a large repertoire of expression of toll-like receptors (TLRs). Activation of these receptors is crucial to detect invading pathogens by the innate immune system. In the present work, we analysed the TLR responsiveness of fibrocytes, a blood-derived cell type of myeloid origin. Fibrocytes efficiently responded to TLR2, TLR4, and TLR7 ligands as well as to poly (I:C) or viral stimulation by producing high amount of interleukin-6. Upon virus infection of fibrocytes, IFN type I was also induced. When compared to pDC or Flt3 ligand-derived DC, fibrocytes produced 5 times and 60 times more IL-6, respectively. This response was associated with a rapid and efficient translocation of the NF-kappaB transcription factor. Analysis of the expression and functionality of TLR7 in peripheral blood leukocyte subpopulations suggested that this receptor is expressed and functional in a CD163(+) monocytic cell subpopulation containing the fibrocyte precursors. Considering the rapid entry of fibrocytes into wounds, this efficient responsiveness to TLR danger signals, reflects a potentially important role of these cells in the first line of defence against pathogen invasion following traumata.
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PMID:Responsiveness of fibrocytes to toll-like receptor danger signals. 1808 71


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