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)

c-kit is expressed on hematopoietic stem cells and progenitor cells, but not on lymphohematopoietic differentiated cells. Lineage marker-negative, c-kit-positive (Lin-c-kit+) bone marrow cells were fractionated by means of Ly6A/E or Sca-1 expression. Lin-c-kit+Sca-1+ cells, which consisted of 0.08% of bone marrow nucleated cells, did not contain day-8 colony-forming units-spleen (CFU-S), but 80% were day-12 CFU-S. One hundred cells rescued the lethally irradiated mice and reconstituted hematopoiesis. On the other hand, 2 x 10(3) of Lin-c-kit+Sca-1- cells formed 20 day-8 and 11 day-12 spleen colonies, but they could not rescue the lethally irradiated mice. These data indicate that Lin-c-kit+Sca-1+ cells are primitive hematopoietic stem cells and that Sca-1-cells do not contain stem cells that reconstitute hematopoiesis. Lin-c-kit+Sca-1+ cells formed no colonies in the presence of stem cell factor (SCF) or interleukin-6 (IL-6), and only 10% of them formed colonies in the presence of IL-3. However, approximately 50% of them formed large colonies in the presence of IL-3, IL-6, and SCF. Moreover, when single cells were deposited into culture medium by fluorescence-activated cell sorter clone sorting system, 40% of them proliferated on a stromal cell line (PA-6) and proliferated for more than 2 weeks. In contrast, 15% of the Lin-c-kit+Sca-1-cells formed colonies in the presence of IL-3, but no synergistic effects were observed in combination with SCF plus IL-6 and/or IL-3. Approximately 10% proliferated on PA-6, but most of them degenerated within 2 weeks. The population ratio of c-kit+Sca-1+ to c-kit+Sca-1- increased 2 and 4 days after exposure to 5-fluorouracil (5-FU). These results are consistent with the relative enrichment of highly proliferative colony-forming cells by 5-FU. These data show that, although c-kit is found both on the primitive hematopoietic stem cells and progenitors, Sca-1+ cells are more primitive and respond better than Sca-1- cells to a combination of hematopoietic factors, including SCF and stromal cells.
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PMID:In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. 128 87

Our present study was designed to clarify the mechanism by which the same megakaryocyte progenitor cells respond to various cytokines at different stages of megakaryocyte development. We examined the changes in mRNA expression of granulocyte macrophage colony-stimulating factor receptor beta-subunit (GM-CSFR beta-subunit), which was a common subunit of a high-affinity interleukin-3 receptor (IL-3R) and a high-affinity GM-CSFR, and interleukin-6 receptor (IL-6R) during megakaryocyte development in a human megakaryocytic leukemia cell line (CMK) which could proliferate and/or differentiate in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), IL-3, GM-CSF, and IL-6. We found that GM-CSFR beta-subunit mRNA was expressed constitutively in CMK cells and was transiently down-regulated by TPA and IL-6, while the expression of IL-6R mRNA was increased by TPA in association with the differentiation of megakaryocytes. Furthermore, the TPA-induced down-regulation of GM-CSFR beta-subunit mRNA expression and its recovery were blocked by cycloheximide (CHX), a protein synthesis inhibitor, suggesting that these modulations required de novo protein synthesis. These findings imply that multi-lineage cytokines such as GM-CSF and IL-3 may contribute preferentially to the regulation of the earlier development of megakaryocyte progenitor cells with high densities of multi-lineage cytokine receptors, while IL-6 may be limited in its action to supporting the maturation of more differentiated megakaryocyte progenitor cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of GM-CSF receptor beta-subunit and interleukin-6 receptor mRNA expression in a human megakaryocytic leukemia cell line. 129 Sep 64

Entry into the cell cycle of dormant hematopoietic progenitors appears to be regulated by multiple synergistic factors, including interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), IL-11, and the ligand for c-kit, which is also known as steel factor (SF). We have tested the effects of these and other hematopoietic factors on the proliferation of partially enriched dormant murine progenitors in the presence and absence of serum. In serum-containing cultures, SF and IL-11 interacted to support the formation of multilineage colonies; the level of colony formation was comparable with the colony formation supported by other effective two-factor combinations. In serum-free cultures, colony formation supported by two factors was significantly less than that in serum-containing culture and the most effective two-factor combination in serum-free culture was SF plus IL-3. In serum-free cultures, three-factor combinations consisting of SF, IL-3, and one of IL-6, G-CSF, or IL-11 yielded colony formation that was comparable with that seen in serum-containing cultures. These studies indicate that IL-11 belongs to a group of early-acting hematopoietic synergistic factors that now includes IL-6, G-CSF, and IL-11. In contrast, SF is unique among the synergistic factors in that it interacts either with growth factors such as IL-3 or GM-CSF or with synergistic factors such as IL-6, IL-11, or G-CSF.
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PMID:Enhancement of murine hematopoiesis by synergistic interactions between steel factor (ligand for c-kit), interleukin-11, and other early acting factors in culture. 137 16

The "stromal" or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3-specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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PMID:Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma. 137 43

The murine myeloproliferative syndrome induced by the myeloproliferative sarcoma virus (MPSV) has numerous similarities to human primary myelofibrosis. We have shown that medium conditioned by spleen cells of MPSV-infected mice has the capacity to support the growth of primitive blast cell colonies. The detection of this activity associated with MPSV infection stimulated us to characterize the hematopoietins responsible for this activity. Northern blot analysis showed a large increase, or induction, of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (CSF-1), and granulocyte-CSF (G-CSF) transcripts in the hematopoietic organs of MPSV-infected mice; however, no IL-3 transcript could be detected in either MPSV-infected or normal mice. Significant levels of IL-1 alpha, IL-6, G-CSF, and CSF-1 bioactivities were found in the serum of MPSV-infected mice, but not in controls. Additionally, analysis of medium conditioned by spleen cells of MPSV-infected mice showed the presence of tumor necrosis factor alpha bioactivity. The increased production of cytokines that are able to stimulate pluripotent hematopoietic stem cells corroborates the hypothesis of a possible involvement of hematopoietic growth factors in the development of some myeloproliferative disorders.
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PMID:Enhanced hematopoietic growth factor production in an experimental myeloproliferative syndrome. 137 44

Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.
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PMID:Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells. 138 3

Studies on the structure of haemopoiesis in acute myeloblastic leukaemia (AML) has shown the presence of a small population of malignant cells with extensive proliferative and self-renewal properties which are features of stem cells. The requirements of these cells for proliferation have been studied both in clonogenic assays in semi-solid media and in liquid suspension culture. These have demonstrated that AML clonogenic cells from the majority of patients, can be stimulated to proliferate by colony-stimulating factors (GM-CSF, G-CSF and IL-3) as well as other cytokines including interleukin-1 and interleukin-6, all of which are known to stimulate normal haemopoietic progenitors. Unlike normal haemopoietic cells, leukaemic blasts from many patients with AML express transcripts for haemopoietic growth factors including GM-CSF, G-CSF and IL-1 but not IL-3, and secrete growth factor protein. When leukaemic cells are cultured at sufficiently high density to permit cell-cell interactions, autonomous growth of clonogenic cells can be seen. Autonomous growth is related to the autocrine secretion of haemopoietic growth factors including GM-CSF, G-CSF and IL-6. The degree of autonomous colony growth is variable but approximately 70% of AML samples exhibit either partial or totally autonomous growth; the remaining cells being absolutely dependent on exogenous CSF or fail to grow in the culture systems employed. Similar patterns of growth have been found in murine haemopoietic cells lines which have been transformed as the result of the retroviral insertion of genes for GM-CSF or IL-3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autocrine growth factors and leukaemic haemopoiesis. 142 83

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are multifunctional cytokines with many similar activities. LIF is structurally and functionally related to another cytokine, Oncostatin M (OSM), that binds to the high-affinity LIF receptor but not to the low-affinity LIF receptor. A complementary DNA was isolated that encodes the high-affinity converting subunit of the LIF receptor. The converter conferred high-affinity binding of both LIF and OSM when expressed with the low-affinity LIF receptor and is identical to the signal transducing subunit of the IL-6 receptor, gp130. The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells. This receptor system resembles the high-affinity receptors for granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5, which share a common subunit.
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PMID:The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. 154 94

We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation, terminal differentiation, and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast-like elements, interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+, produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta, and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures, monoclonal B lymphocytes and plasma cells, derived from PBMC, developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes, plasma cells, and osteoclasts and the in vivo dissemination of MM.
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PMID:'Role of bone marrow stromal cells in the growth of human multiple myeloma. 167 30

Leukemia inhibitory factor (LIF)/differentiation-inhibiting activity (DIA)/human interleukin for DA cells (HILDA) is a cytokine with biologic activities involving a variety of different types of target cells. Here we have tested LIF/DIA for possible effects on the growth and differentiation of normal human hematopoietic cells in culture. As a single agent, LIF/DIA had no effect on colony formation by CD34-positive human bone marrow cells. However, LIF/DIA was as effective as either interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the enhancement of IL-3-dependent colony formation of very primitive blast colony-forming cells. Studies using neutralizing antibodies against IL-6 or G-CSF demonstrated that this was not due to induction in culture of either of the other known synergistic factors for blast cell colony formation. A 1-day delay in the time course of appearance of blast cell colonies grown in the presence of LIF/DIA relative to those grown in the presence of IL-6 suggests that the different synergistic factors may operate through different mechanisms, although we cannot rule out that high doses of LIF/DIA might yield accelerated blast cell colony formation. Our findings provide evidence that LIF/DIA may play an important role, along with IL-6 and G-CSF, in the regulation of early hematopoietic stem cells.
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PMID:Leukemia inhibitory factor differentiation-inhibiting activity/human interleukin for DA cells augments proliferation of human hematopoietic stem cells. 169 90


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