UNIPROT:P05231 - FACTA Search

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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 previously shown that early human CD34high hematopoietic progenitors are maintained quiescent in part through autocrine transforming growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the presence of interleukin-3, interleukin-6, granulocyte colony-stimulating factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocrine TGF-beta 1 might suppress c-kit expression in primitive human hematopoietic progenitors. We have now distinguished two subpopulations of CD34high cells. One subpopulation expresses a c-kit mRNA that can be downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early CD34high cells expresses a low or undetectable level of c-kit mRNA, but its expression can be upmodulated within 6 hours by anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF-beta 1 or anti-TGF-beta serum are added every day. Similar kinetics, although delayed, are observed with KIT protein expression. On the contrary, no specific effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results clarify the complex interaction between TGF-beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to maintain these cells in a quiescent state, suppressing cell division by downmodulating the receptor of SF, a key cytokine costimulator of early progenitors.
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PMID:Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit. 754 39

Both normal and leukaemic human megakaryocytopoiesis are stimulated by several cytokines, including stem cell factor, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3, GM-CSF/interleukin-3 fusion protein, interleukin-6, interleukin-11, basic fibroblast growth factor and thrombopoietin, but are inhibited by tumour necrosis factor-alpha, platelet factor 4, beta-thromboglobulin, thrombin, interleukin-4, interferon-alpha and interferon-gamma. Human megakaryoblastic leukaemia cell lines have common biological features, including high expression of the megakaryocytic specific antigen: CD41; high expression of the early myeloid antigens: CD34 and CD33; constitutive expression of interleukin-6 and platelet-derived growth factor; complex karyotype picture; expression of c-kit: the stem cell factor receptor; growth-dependency or -stimulation by stem cell factor, interleukin-3 and/or GM-CSF; megakaryoblastic differentiation by phorbol-myristate-acetate; and in vivo tumorigenicity in mice is associated with marked fibrosis. Only a few agents including phorbol-myristate-acetate; vitamin D3, interferon-alpha, interferon-beta 2, erythropoietin and thrombin have been reported to induce megakaryocytic differentiation in the human megakaryoblastic leukaemia cells.
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PMID:Characteristic biological features of human megakaryoblastic leukaemia cell lines. 756 68

Monocytes and macrophages show marked phenotypic variation dependent on their tissue of origin. Peripheral blood monocytes have been found to be sources of a variety of cytokines, but isolated marrow macrophages have not been characterized in this regard. Marrow macrophages form a predominant component of murine adherent Dexter stromal cells and can be isolated by sequential explant culture in colony-stimulating factor-1 (CSF-1). We have studied murine (Balb/c) bone marrow macrophage (BMM) cytokine production in the presence or absence of CSF-1, the lectin pokeweed mitogen (PWM) or interleukin-3 (IL-3). Biologic activity in conditioned media (cm) from control and induced BMM was assessed using the factor-dependent cell lines 32D, NFS-60, T1165, MC-6 and FDC-P1. Cell line stimulation and antibody blocking indicated the presence of c-kit ligand, interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). This stimulatory activity was increased by exposure to PWM or the combination of CSF-1 and PWM or CSF-1 and IL-3. CSF-1, as determined by radioimmunoassay (RIA), was essentially undetectable in baseline cm and induction was not seen with PWM or CSF-1. Baseline or "constitutive" expression of BMM and mRNA for CSF-1 and c-kit ligand was seen. Uninduced BMM did not express mRNA for G-CSF, granulocyte-macrophage CSF (GM-CSF), IL-6 or IL-3. CSF-1 induced increased expression of IL-6 mRNA, PWM induced increased expression of G-CSF and IL-6 mRNA and the combination of PWM and CSF-1 induced expression of CSF-1, G-CSF and IL-6 mRNA. Varying levels of CSF-1 had differential effects on cytokine production. Increasing levels of CSF-1 increased IL-6 mRNA and downmodulated CSF-1 mRNA expression. There was a biphasic response of c-kit ligand mRNA expression to CSF-1 exposure; low levels of CSF-1 (50 U/mL) induced, while higher levels (2000 U/mL) inhibited, expression. These data indicate that BMM (and by analogy the macrophage component of Dexter culture stroma), are important sources of CSF-1 and c-kit ligand but not GM-CSF or IL-3. BMM can also be induced to express IL-6 and/or G-CSF. Lastly, CSF-1, by differentially modulating BMM cytokine production in a holocrine or autocrine manner, may function as a central regulator of stromal based hematopoiesis.
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PMID:Cytokine expression from bone marrow derived macrophages. 767 17

To study the role of different cytokine combinations on the proliferation and differentiation of highly purified primitive progenitor cells, a serum-free liquid culture system was used in combination with phenotypic and functional analysis of the cells produced in culture. CD34+ CD45RAlo CD71lo cells, purified from umbilical cord blood by flow cytometry and cell sorting, were selected for this study because of their high content of clonogenic cells (34%), particularly multipotent progenitors (CFU-MIX, 12% of all cells). Four cytokine combinations were tested: (1) mast cell growth factor (MGF; a c-kit ligand) and interleukin-6 (IL-6); (2) MGF, IL-6, IL-3, and erythropoietin (Epo); (3) MGF, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-3 fusion protein (FP), macrophage colony-stimulating factor (M-CSF), and granulocyte-CSF (G-CSF); and (4) MGF, IL-6, FP, M-CSF, G-CSF, and Epo. Maximum numbers of erythroid progenitors (BFU-E, up to 55-fold increase) and mature erythroid cells were observed in the presence of MGF, IL-6, IL-3, and Epo, whereas maximum levels of myeloid progenitors (CFU-C, up to 70-fold increase) and mature myeloid cells were found in cultures supplemented with MGF, IL-6, FP, M-CSF, and G-CSF. When MGF, IL-6, FP, M-CSF, G-CSF, and Epo were present, maximum levels of both erythroid and myeloid progenitors and their progeny were observed. These results indicate that specific cytokine combinations can act directly on primitive hematopoietic cells resulting in significant expansion of progenitor cell numbers and influencing their overall patterns of proliferation and differentiation. Furthermore, the observations presented in this study suggest that the cytokine combinations used were unable to bias lineage commitment of multipotent progenitors, but rather had a permissive effect on the development of lineage-restricted clonogenic cells.
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PMID:Cytokine-induced selective expansion and maturation of erythroid versus myeloid progenitors from purified cord blood precursor cells. 768

The monoclonal rat anti-c-kit antibody (ACK2), which abrogates colony growth supported by stem cell factor (SCF), significantly inhibited the interleukin-6 (IL-6)-dependent growth of hematopoietic progenitors derived from spleen cells of normal and 5-fluorouracil (5-FU)-treated mice and from bone marrow cells of normal mice in serum-containing culture. The numbers and types of colonies supported by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), however, were not influenced by the addition of ACK2 to the cultures of the bone marrow cells from normal mice. In replating experiments with pooled blast cells, ACK2 caused a partial, but significant, inhibition of GM colony growth supported by a combination of IL-6 and fetal bovine serum (FBS), which suggests that FBS is one source of the SCF activity. Conversely, the addition of SCF or FBS with IL-6 to a serum-free culture had significant synergistic effects on the total number of colonies derived from post-5-FU spleen cells and from pooled blast cells. The dose response study showed that the ability of 30% FBS to interact with IL-6 on the colony growth by post-5-FU spleen cells was equivalent to that of approximately 5 ng/mL SCF. These findings suggest that c-kit plays an important role in the growth of hematopoietic progenitors responding to IL-6, and that SCF in the serum affects the development of hematopoietic progenitors in serum-containing cultures.
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PMID:Possible role of stem cell factor as a serum factor: monoclonal anti-c-kit antibody abrogates interleukin-6-dependent colony growth in serum-containing culture. 768 4

We previously described that cells with a CD34+CD71lo phenotype from adult human bone marrow are maintained at constant numbers in long-term suspension cultures supplemented with interleukin-6 (IL-6), IL-3, mast growth factor (MGF) (a c-kit ligand), and erythropoietin (Epo). In view of the large increase in cell numbers in such cultures (for example, > 10(6)-fold per cell), this was an unexpected finding. The following models for the observed maintenance of CD34+CD71lo cells in our cultures were considered: (1) survival of non-dividing cells; (2) self-renewal balanced by loss of cells; (3) asymmetrical divisions; and (4) combinations of the above. Two experimental strategies were explored to discriminate between these models. In the first, sorted CD34+CD45RAloCD71lo cells were labeled with the flourescent tracking dye PKH26, followed by analysis of PKH26 fluorescence of CD34+CD71lo and other cells present in the cultures at various times (up to 11 weeks). In the second approach, single CD34+CD45RAloCD71lo cells were directly sorted into individual wells, and growing cells were then analyzed by flow cytometry. Results from these experiments indicated a considerable variability in (1) the number of surviving input cells (ranging from 30 to 80%); (2) the proportion of cells that contributed significantly to the total cell production measured at day 20 (ranging from 1 to 5%); and (3) the number of CD34+ cells present in individual clones. Taken together, the observed maintenance of primitive CD34+ cells in our cultures apparently involves a combination of survival of CD34+CD71lo cells with a vary low turnover together with a very limited production of CD34+ cells. Clonal heterogeneity, differences in cell cycle kinetics between CD34+ and CD34- cells, and observations that the majority of bone marrow-derived CD34+CD45RAloCD71lo cells do not show a rapid proliferative response to a mixture of IL-6, IL-3, MGF, and Epo will have to be taken into account in the development of experimental strategies aimed at clinically useful expansion of primitive hematopoietic cells ex vivo.
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PMID:Maintenance of hematopoiesis in serum-free bone marrow cultures involves sequential recruitment of quiescent progenitors. 768 81

To clarify the phenotypes of various classes of human hematopoietic progenitor cells, we used a multicolor staining protocol in conjunction with CD34 and a newly developed mouse antihuman c-kit proto-oncogene product (KIT) monoclonal antibody (MoAb). We characterized three cell fractions in CD34+ cells that express KITlow and KIThigh cells in addition to KIT- cells. A clonogenic assay showed that most granulocyte-macrophage colony-forming cells (GM-CFC) were present in CD34+KIThigh populations, whereas erythroid burst-forming cells (BFU-E) were detected mainly in the CD34+KITlow population. CD34(+)-KIT- fraction contained a small number of BFU-E. Morphologic analysis showed that blast-like cells were more enriched in the CD34+KITlow fraction. KITlow cells contained CD34+CD38- cells that were considered to be very primitive progenitor cells, as determined by a replating assay. To clarify the biologic differences between both fractions, we examined the more primitive progenitor cell functions by assessing long-term culture-initiating cells (LTC-IC) on the stromal cells. At week 2, more CFC recovered from the culture in the fraction initiated with a CD34+KIThigh population. However, more LTC-IC were present during weeks 5 to 9 in the CD34+KITlow population. These results indicate that primitive progenitors are more enriched in the KITlow population and that the KIThigh population contains many GM-committed progenitor cells. We also showed that anti-KIT MoAb inhibited the ability of CD34+ cells to generate CFC on the stromal layer in the LTC system. This suppressive effect was more evident in the generation of BFU-E by CD34+KITlow cells. Moreover, we confirmed that CD34+KIThigh cells emerged from CD34+KITlow cells during coculture with allogeneic stromal cells or from liquid culture in the presence of stem cell factor (SCF), interleukin-6, and erythropoietin. These results emphasize the pivotal role of the KIT and SCF interaction in hematopoiesis and indicate that KITlow cells are more primitive than KIThigh cells.
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PMID:Human primitive hematopoietic progenitor cells are more enriched in KITlow cells than in KIThigh cells. 769 77

The development of clinically frank malignant melanomas in humans is thought to evolve over decades in a stepwise process of progression. By analogy with certain other adult cancers, eg, colorectal carcinomas, alterations in expression or function of a number of different suppressor genes might be expected to be involved in this process. This could lead to loss of expression of a number of different negative growth controls. Evidence is reviewed implicating the presence of putative suppressor genes for the melanocytic lineage located on chromosomes 9p21, 6q, and 1p. In addition, there is evidence suggesting a contribution for the p53 and NF1 tumor-suppressor genes, and the nm23 metastasis-suppressor gene, in melanoma development or progression. Additional possible suppressor genes include those encoding manganese superoxide dismutase, and possibly c-kit. An accumulation of such alterations may be responsible for the progressive loss of responsiveness to several independent growth inhibitors for melanocytes or early stage melanomas, including interleukin-6, transforming growth factor-beta, and oncostatin M. They may also be responsible for some aspects of the production of direct acting autocrine growth factors or production of angiogenesis stimulating factors, or both, by melanoma cells. The acquisition of resistance to several growth inhibitors and the multiplicity of putative suppressor gene alterations (combined with the production of multiple autocrine and paracrine growth factors) may be necessary for the evolution of nondividing single melanocytes resident in the epidermis into highly proliferative and metastatic melanomas capable of growing multicellularly in ectopic organ sites.
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PMID:Cytokines, growth factors and the loss of negative growth controls in the progression of human cutaneous malignant melanoma. 801 99

Human umbilical cord blood (CB) appears to be an exciting new source of transplantable stem cells for a variety of clinical conditions. In this study, we have attempted to further characterize the primitive progenitors in CB. First we analyzed the effects of early-acting growth factors on blast cell colony formation from CD34+ progenitors. Addition of Steel factor (SF), interleukin-6 (IL-6), or granulocyte colony-stimulating factor (G-CSF) to cultures containing interleukin-3 enhanced blast cell colony formation. These results indicated that cell cycle-dormant progenitors are present in CB. Next, based on results obtained in the murine system, we tested whether c-kit expression could separate the CB progenitors into cycle-dormant vs. cycle-active progenitors. Cells were separated into CD34+ c-kit-, c-kitlow, and c-kithigh. The results suggested that the c-kitlow population contains the majority of cycle-dormant progenitors and the c-kithigh population contains most of the forming cells were in the c-kitlow population, while the opposite is true for other colony-forming cells. Expression of c-kit may be useful in identifying CB progenitors with long-term engraftment capability.
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PMID:Characterization of c-kit expression by primitive hematopoietic progenitors in umbilical cord blood. 854 40

We investigated the effects of stem cell factor (SCF) on the growth of blast clonogenic cells from 27 patients with acute myeloblastic leukemia (AML) and 3 patients with chronic myelocytic leukemia in myeloid crisis. SCF alone showed a significant stimulatory activity in 15 of 30 patients (50%). A marked reduction in the number of blast cell colonies supported by SCF alone was noted by the addition of neutralizing antibody (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF). Ab against interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) also moderately reduced the number of colonies, whereas Ab against granulocyte CSF (G-CSF) failed to do so. All four Ab together completely abolished the growth in 5 of 6 patients tested. c-kit antisense oligonucleotides reduced the colony formation supported by IL-3 or G-CSF or, in the absence of growth factor, in only 2 of 10 patients tested. SCF caused stimulation by acting synergistically with G-CSF, GM-CSF, IL-3, IL-6, IL-9, IL-11, and IL-12 in 20 of 27 (74%), 17 of 27 (63%), 14 of 28 (50%), 9 of 28 (32%), 1 of 15 (7%), 3 of 28 (11%), and 2 of 15 (13%) patients, respectively. Thus, SCF alone or in combination with some other factor stimulated the growth in 27 of 30 (90%) patients. Of 3 nonresponders, 2 were AML, M3 at presentation. G-CSF at the optimal concentration increased the sensitivity of blasts to SCF. Taken together, SCF acting in combination with other factors, but not alone, stimulates the growth of blast clonogenic cells. GM-CSF, IL-6, and TNF-alpha may be produced endogenously, whereas G-CSF and SCF may be supplied exogenously. Autocrine regulation of the growth of blasts seems to increase the responsiveness of the cells to any of these factors, allowing them to achieve a highly active growth state.
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PMID:Roles of stem cell factor in the in vitro growth of blast clonogenic cells from patients with acute myeloblastic leukemia. 856 3

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