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John W Schrader - One of the best experts on this subject based on the ideXlab platform.
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cross-linking of the B-lymphocyte receptor for antigen
2016Co-Authors: Brock Grill, John W SchraderAbstract:Rac-1 was also activated by colony-stimulating factor-1 (CSF-1), Steel locus factor (SLF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 or by cross-linking the B-lymphocyte receptor for antigen (BCR). The activation of Rac-1 induced by cross-linking the BCR or by IL-3 stimulation was blocked only partially by Ly294002, with about 25 % to 30 % of Rac-1 activation still occur-ring in the absence of detectable in-creases in phosphatidyl-inositol-3 kinase (PI-3K) activity. Overexpression of consti-tutively active mutants of H-Ras, N-Ras, or M-Ras resulted in activation of coex-pressed Rac-1 through an Ly29402-resistant, PI-3K–independent mechanism. Overexpression of constitutively active mutants of p21 Ras, or Rac-1, but not of PI-3K, was sufficient for activation of p38 mitogen-activated protein kinase (MAPK) in cells of Hemopoietic origin. Inhibition of increases in PI-3K activity by Ly294002 had no effect on the IL-3–induced activa-tion of p38 MAPK. In contrast, Ly294002 partially inhibited the activation of p38 MAPK induced by cross-linking of the BCR, although some p38 MAPK activation oc-curred in the absence of increases in the activity of Rac-1 or PI-3K. The activation of Rac-1, Rac-2, and Cdc42 by IL-3 and other Hemopoietic Growth Factors is likely to be an important component of their actions in promoting Growth, survival, and function
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activation of rac 1 rac 2 and cdc42 by Hemopoietic Growth Factors or cross linking of the b lymphocyte receptor for antigen
Blood, 2002Co-Authors: Brock Grill, John W SchraderAbstract:Interleukin-3 (IL-3)–induced activation of endogenous Rac-1, Rac-2, and Cdc42. Rac-1 was also activated by colonystimulating factor-1 (CSF-1), Steel locus factor (SLF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 or by cross-linking the B-lymphocyte receptor for antigen (BCR). The activation of Rac-1 induced by cross-linking the BCR or by IL-3 stimulation was blocked only partially by Ly294002, with about 25% to 30% of Rac-1 activation still occurring in the absence of detectable increases in phosphatidyl-inositol-3 kinase (PI-3K) activity. Overexpression of constitutively active mutants of H-Ras, N-Ras, or M-Ras resulted in activation of coexpressed Rac-1 through an Ly29402resistant, PI-3K–independent mechanism. Overexpression of constitutively active mutants of p21 Ras, or Rac-1, but not of PI-3K, was sufficient for activation of p38 mitogen-activated protein kinase (MAPK) in cells of Hemopoietic origin. Inhibition of increases in PI-3K activity by Ly294002 had no effect on the IL-3–induced activation of p38 MAPK. In contrast, Ly294002 partially inhibited the activation of p38 MAPK induced by cross-linking of the BCR, although some p38 MAPK activation occurred in the absence of increases in the activity of Rac-1 or PI-3K. The activation of Rac-1, Rac-2, and Cdc42 by IL-3 and other Hemopoietic Growth Factors is likely to be an important component of their actions in promoting Growth, survival, and function. (Blood. 2002;100:3183-3192)
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Hemopoietic Growth Factors with the Exception of Interleukin-4 Activate the p38 Mitogen-activated Protein Kinase Pathway
The Journal of biological chemistry, 1997Co-Authors: Ian Foltz, John C. Lee, Peter Young, John W SchraderAbstract:Abstract The mammalian mitogen-activated protein (MAP) kinase homologue p38 has been shown to be activated by pro-inflammatory cytokines as well as physical and chemical stresses. We now show that a variety of Hemopoietic Growth Factors, including Steel locus factor, colony stimulating factor-1, granulocyte/macrophage-colony stimulating factor, and interleukin-3, activate p38 MAP kinase and the downstream kinase MAPKAP kinase-2. Furthermore, although these Growth Factors activate both p38 MAP kinase and Erk MAP kinases, we demonstrate using a specific inhibitor of p38 MAP kinase, SB 203580, that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation. Conversely p38 MAP kinase was shown not to be required for in vivo activation of p90rsk, known to be downstream of the Erk MAP kinases. Interleukin-4 was unique among the Hemopoietic Growth Factors we examined in failing to induce activation of either p38 MAP kinase or MAP kinase-activated protein kinase-2. These findings demonstrate that the activation of p38 MAP kinase is involved not only in responses to stresses but also in signaling by Growth Factors that regulate the normal development and function of cells of the immune system.
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multiple Hemopoietic Growth Factors stimulate activation of mitogen activated protein kinase family members
Journal of Immunology, 1992Co-Authors: M J Welham, Vincent Duronio, J S Sanghera, Steven L Pelech, John W SchraderAbstract:Stimulation of Hemopoietic cells with IL-3, IL-4, IL-5, granulocyte-macrophage-CSF and Steel factor-(SLF) induced tyrosine phosphorylation of a number of protein substrates. Two of these proteins, designated p42 and p44, were tyrosine phosphorylated rapidly in response to treatment with IL-3, IL-5, granulocyte-macrophage-CSF and SLF, but not IL-4. We demonstrate that these common substrates are members of the mitogen-activated protein kinase (MAP kinase) family of protein serine/threonine kinases. Ion-exchange chromatography yielded a peak of MAP kinase activity eluting at 0.3 to 0.32 M NaCl. Immunoblotting of column fractions with antiphosphotyrosine antibodies showed coelution of the peak of MAP kinase enzyme activity with the p42 and p44 tyrosine phosphorylated species, and with two proteins of 42 and 44 kDa which were immunoreactive with anti-MAP kinase antibodies. Moreover, a characteristic shift in mobility of the p42 and p44 species was observed after factor treatment. Time-course analyses and subsequent ion-exchange chromatography demonstrated SLF activation of MAP kinase activity was maximal after 2 min of factor treatment and decreased to basal levels after 30 min stimulation. By contrast, activation of MAP kinase after IL-5 treatment was not as rapid. Maximal activity was observed 15 min after stimulation and remained elevated for up to 60 min after IL-5 addition. Investigation of the role of protein kinase C in the mechanism of activation by these Growth Factors demonstrated that specific inhibition of protein kinase C led to a reduction, but not ablation, of the SLF and IL-3 induced stimulation of MAP kinase activity. The use of synthetic peptide substrates confirmed SLF and IL-5 activate isoforms of MAP kinases. These results demonstrate that members of the MAP kinase family are involved in common signal transduction events elicited by IL-3, IL-5, granulocyte-macrophage-CSF and Steel factor, but not those involving IL-4.
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Modulation of c-kit mRNA and protein by Hemopoietic Growth Factors.
Molecular and cellular biology, 1991Co-Authors: M J Welham, John W SchraderAbstract:Abstract We examined the effects of various hemopoietins on c-kit mRNA and protein expression. Interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and erythropoietin, but not IL-4, down-regulated levels of c-kit mRNA expressed by mast cells and stem cell progenitors. The effect of IL-3 was dominant and independent of cell Growth or viability and was paralleled by reduced expression in c-kit protein. These observations indicate that regulation of c-kit expression is closely interlinked with the molecular mechanisms triggered by erythropoietin, IL-3, and granulocyte-macrophage colony-stimulating factor.
J Tikerpae - One of the best experts on this subject based on the ideXlab platform.
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interactions of tumor necrosis factor with granulocyte macrophage colony stimulating factor and other cytokines in the regulation of dendritic cell Growth in vitro from early bipotent cd34 progenitors in human bone marrow
Journal of Immunology, 1992Co-Authors: C D L Reid, Arthur Stackpoole, A Meager, J TikerpaeAbstract:Colonies of CD1a+ HLA-DR+/DQ+ CD4+ cells with the functional and some of the structural attributes of Langerhans cells are observed in human bone marrow cultures in semi-solid media and are assumed to be the progeny of an early progenitor, the dendritic/Langerhans cell CFU (CFU-DL). The cytokine-regulated Growth of these cells has been studied using a chemically defined serum-free system to culture both unfractionated and highly enriched bone marrow progenitor cell populations. Although unfractionated cell Growth was optimal in serum replete cultures with PHA-stimulated leukocyte-conditioned medium (PHA-LCM) suboptimal proliferation of CFU-DL was observed in serum even in the absence of PHA-LCM. No colonies were observed under serum-free conditions when granulocyte-macrophage CSF (GM-CSF), IL-3, granulocyte CSF (G-CSF), and macrophage CSF (M-CSF) were present at levels optimal for granulocyte colony-forming unit (CFU-G) and macrophage colony-forming unit (CFU-M) Growth. Addition of IL-1 alpha to these cytokines stimulated a small number of CFU-DL. However, in the presence of GM-CSF and IL-3, TNF-alpha or TNF-beta (5 U/ml) were both highly effective in promoting Growth up to 82% of optimal and CFU-G Growth was also enhanced at these concentrations. TNF was only active during the first 3 days of culture and higher concentrations of TNF-alpha but not TNF-beta were inhibitory for both CFU-DL and CFU-G. CD34+ cell-enriched populations were also enriched for both myeloid progenitors (CFU-G + CFU-M) and CFU-DL to 36- and 48-fold, respectively, and single cell cultures of CD34+ cells yielded single colonies containing both CD1a+ dendritic cells and CD1a- macrophages. Thus dendritic/Langerhans progenitors in the bone marrow expresses CD34, have a capacity for both macrophage and dendritic cell differentiation, and depend on Hemopoietic Growth Factors and TNF for their further development in vitro.
D Metcalf - One of the best experts on this subject based on the ideXlab platform.
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Role of Hemopoietic Growth Factors in the development and suppression of myeloid leukemia.
Leukemia, 1992Co-Authors: D MetcalfAbstract:Myeloid leukemia development requires the acquisition by a cell of two abnormalities: an abnormal capacity for self-replication; and a capacity for autocrine stimulation, usually involving the known Growth Factors for granulocyte-macrophage cells. Curiously, in human leukemia, this does not usually result in autonomous Growth when assessed in clonal in vitro cultures. Depending on gene programming, in particular in human or murine myeloid leukemias, the Hemopoietic Growth Factors can also suppress the leukemic population by inhibiting the capacity of the leukemic stem cells for self-generation. The regulator showing the highest suppressive activity varies from leukemia to leukemia, with G-CSF. GM-CSF, IL-6, or leukemia-inhibitory factor (LIF) all having high activity on appropriate target cells. Combinations of these regulators are more effective than single agents alone. Analyses of human HL60, U937 and murine M1 leukemic models indicate that the development of morphological maturation in the leukemic cells is not a necessary feature of stem-cell suppression. LIF has an anomalous action on stem-cell self-generation, being highly effective in the suppression of certain myeloid leukemic cell lines, but being necessary to maintain self-generation in normal embryonic cells. This suggests the existence of a common control medium governing self-generation decisions in cells of different lineages, but that the outcome of the decision is determined by the differentiation program operating in different cells. The colony-stimulating Factors are being used in combination with chemotherapy in the treatment of patients with acute myeloid leukemia, but the above principles require caution in certain situations.
Abelardo Lopezrivas - One of the best experts on this subject based on the ideXlab platform.
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insulin like Growth factor i inhibits apoptosis in il 3 dependent Hemopoietic cells
Journal of Immunology, 1992Co-Authors: Gemma Rodrigueztarduchy, Mary Collins, I Garcia, Abelardo LopezrivasAbstract:The death of Hemopoietic cells on withdrawal of CSF occurs by a mechanism known as apoptosis characterized by the early degradation of chromatin into oligonucleosome-length fragments. Insulin-like Growth factor I plays a pivotal role in the regulation of somatic cell Growth as a mediator of Growth hormone action. Animals with low levels of circulating IGF-I are more vulnerable to infections and have diminished immune responses. To analyze the possibility of a regulatory role of IGF-I on hemopoiesis and determine its mechanism of action, we have studied the effect of this Growth factor on the survival and proliferation of two IL-3-dependent Hemopoietic cell lines and in IL-3-responsive primary cultures of bone marrow-derived mast cells. In IL-3-depleted cultures, IGF-I prevented DNA fragmentation and apoptotic cell death. Insulin at high concentration had a weak protective action and IGF-II was inactive in suppressing apoptosis in these IL-3-dependent Hemopoietic cells. Cell proliferation was also stimulated by IGF-I in the absence of other Hemopoietic Growth Factors although it was a weak mitogen when compared with IL-3. These results indicate that circulating or locally produced IGF-I may promote survival of both the steady state Hemopoietic precursor population and cytokine-producing cells and could therefore regulate hemopoiesis acting in a concerted manner with other CSF.
C D L Reid - One of the best experts on this subject based on the ideXlab platform.
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interactions of tumor necrosis factor with granulocyte macrophage colony stimulating factor and other cytokines in the regulation of dendritic cell Growth in vitro from early bipotent cd34 progenitors in human bone marrow
Journal of Immunology, 1992Co-Authors: C D L Reid, Arthur Stackpoole, A Meager, J TikerpaeAbstract:Colonies of CD1a+ HLA-DR+/DQ+ CD4+ cells with the functional and some of the structural attributes of Langerhans cells are observed in human bone marrow cultures in semi-solid media and are assumed to be the progeny of an early progenitor, the dendritic/Langerhans cell CFU (CFU-DL). The cytokine-regulated Growth of these cells has been studied using a chemically defined serum-free system to culture both unfractionated and highly enriched bone marrow progenitor cell populations. Although unfractionated cell Growth was optimal in serum replete cultures with PHA-stimulated leukocyte-conditioned medium (PHA-LCM) suboptimal proliferation of CFU-DL was observed in serum even in the absence of PHA-LCM. No colonies were observed under serum-free conditions when granulocyte-macrophage CSF (GM-CSF), IL-3, granulocyte CSF (G-CSF), and macrophage CSF (M-CSF) were present at levels optimal for granulocyte colony-forming unit (CFU-G) and macrophage colony-forming unit (CFU-M) Growth. Addition of IL-1 alpha to these cytokines stimulated a small number of CFU-DL. However, in the presence of GM-CSF and IL-3, TNF-alpha or TNF-beta (5 U/ml) were both highly effective in promoting Growth up to 82% of optimal and CFU-G Growth was also enhanced at these concentrations. TNF was only active during the first 3 days of culture and higher concentrations of TNF-alpha but not TNF-beta were inhibitory for both CFU-DL and CFU-G. CD34+ cell-enriched populations were also enriched for both myeloid progenitors (CFU-G + CFU-M) and CFU-DL to 36- and 48-fold, respectively, and single cell cultures of CD34+ cells yielded single colonies containing both CD1a+ dendritic cells and CD1a- macrophages. Thus dendritic/Langerhans progenitors in the bone marrow expresses CD34, have a capacity for both macrophage and dendritic cell differentiation, and depend on Hemopoietic Growth Factors and TNF for their further development in vitro.