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PubMed1985

Effect of anti-CSF on in vivo hemopoiesis.

Studies were undertaken to determine whether colony-stimulating factor in the serum is important in the control of granulopoiesis and monocytopoiesis. Groups of mice were injected with either antiserum to colony-stimulating factor (CSF) or normal rabbit serum every 12 h for intervals of 6-7 days. Antibody treatment did not lead to a reduction in circulating granulocytes or monocytes nor a decrease in marrow cellularity. In further studies, two dose levels of purified anti-CSF were employed; rabbit IgG served as a control. Virtually no effect was observed on blood monocytes, blood granulocytes, or marrow granulocytes; however, antibody treatment did cause a decline in marrow colony-forming cells and a reciprocal increase in erythroid progenitor cells. Immunoassays showed a virtual absence of serum anti-CSF after five days, despite continued administration of the antibody. Modified immunoassays indicated that this was due to development of murine antibodies directed against anti-CSF. In further experiments, mice received the purified antibody or whole antiserum in conjunction with cortisone to reduce murine antibody formation. Despite persistent anti-CSF levels in the serum, blood granulocytes, blood monocytes, and marrow precursor cells were unaffected. These findings suggest that serum levels of CSF do not appear to be responsible for in vivo granulopoiesis or monocytopoiesis.

Animals↗
PubMed1982

The production of committed hemopoietic colony-forming cells from multipotential precursor cells in vitro.

Murine fetal liver cells have been fractionated by fluorescence-activated cell sorting into two fractions termed. For convenience, the pre-CFC and CFC (colony-forming cell) fractions, which differ in their relative binding of the lectin, pokeweed mitogen. The CFC fraction contained a high frequency of CFC (26%) and in liquid cultures stimulated with colony-stimulating factors generated large numbers of differentiated progeny. Consequently, residual CFC could not be detected in such cultures after day 4. In contrast, the pre-CFC fraction contained relatively few CFC (1%) but contained the majority of CFU-S and was able to generate large numbers of new CFC after 5-7 days in liquid culture. This production of CFC from precursor cells was absolutely dependent on factors present in pokeweed-mitogen-stimulated spleen cell conditioned medium (PWM-SCM) or postendotoxin serum (ES) but was not stimulated by known granulocyte or macrophage colony-stimulating factors. CFC production occurred from multipotential precursor cells and all types of CFC were detected (excluding lymphocytes). Clonal analysis of pre-CFC showed that most of the generated CFC arose from relatively few multipotential precursors some of which could generate up to 500 CFC. The data suggested a differentiation sequence of the multipotential precursor cells in which differentiation potentials are successively restricted in the order macrophage, eosinophil, granulocyte-macrophage leads to granulocyte, megakaryocyte, erythroid. The frequency of CFC-generating cells in the pre-CFC fraction was significantly less (ten-fold) than that of CFU-S, suggesting that pre-CFC may be a more ancestral subset of CFU-S. The cell fractions and assay systems described should be of use in defining and purifying factors regulating early phases of hemopoietic differentiation and in defining the differentiation steps involved in the restriction of potentialities of multipotential cells.

Animals↗
PubMed1994

Effect of human recombinant granulocyte-macrophage colony-stimulating factor and IL-3 on the expression of surface markers of human monocyte-derived macrophages in long-term cultures.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3, which are involved in the maturation of cell precursors in the bone marrow into granulocytes and macrophages, were found also in chronic inflammatory sites, and their production might be enhanced by inflammatory stimulants. These findings led us to examine the effect of human recombinant GM-CSF (hrGM-CSF) and hrIL-3 on the maturation of human peripheral blood monocytes in long-term tissue cultures and on the expression of functional membrane bound molecules. Adherent human peripheral blood monocytes cultured for 2 weeks in the presence of GM-CSF or IL-3 were examined for viability and adherence, expression of membranal HLA-DR, CD-14, and IL-1 alpha, and LPS triggered TNF-alpha production. GM-CSF and IL-3 treatment increased the viability of adherent cells after 2 weeks in culture, and elevated the expression of membranal HLA-DR, CD-14 (LPS receptor), and IL-1 alpha. Such treated macrophage cultures also showed elevated production of TNF-alpha. The results indicate that GM-CSF and IL-3 facilitate the long-term maturation of monocytes into macrophages, augment their capacity to bind LPS, and elevate the release of cytokines involved in inflammatory and granulomatous reactions.

Antigens, CD↗
PubMed2006

Granule targeting of soluble tumor necrosis factor (TNF) receptor expressed during granulopoietic maturation in murine bone marrow cells.

In this experiment, we explored the potential of secretory lysosomes of hematopoietic cells to act as vehicles for immunomodulatory protein delivery at an inflammation site. We investigated whether exogenous soluble TNF-receptor 1 (sTNFR1) could be expressed in primary hematopoietic progenitor cells and become targeted for storage and secretion during granulopoietic differentiation. An sTNFR1 construct with a transmembrane domain (tm) and a cytosol sorting signal (Y) taken from CD63, was retrovirally transduced to lineage-negative murine hematopoietic bone marrow stem/progenitor cells. This process was followed by cytokine-driven granulopoietic maturation. The sTNFR1-tm-Y was found to be synthesized in precursor cells and to persist in mature granulocytes and monocytes/macrophages. Immunofluorescence-localization studies showed a granule pattern of sTNFR1-tm-Y in both precursor and mature granulocytes and secretion to phagosomes after ingestion of bacteria. Immunoelectron microscopy revealed co-localization between the sTNFR1-tm-Y and the primary (azurophil) granule marker myeloperoxidase. Collectively, our results demonstrated granule targeting, storage, and secretion of exogenous sTNFR1-tm-Y constitutively expressed during normal granulopoietic differentiation. These findings support the concept of using storage organelles of circulating hematopoietic cells as vehicles for targeting sites of inflammation with immunoregulatory agents.

Animals↗
PubMed1996

Sensitivity of murine haemopoietic stem cell populations to X-rays and 1 MeV fission neutrons in vitro and in vivo under hypoxic conditions.

The radiosensitivity of primitive haemopoietic stem cells that repopulate the bone marrow with precursors of granulocytes and macrophages (MRA[CFU-C]), mature stem cells capable of forming spleen colonies in lethally irradiated recipients (CFU-S-7) and colony-forming units in culture (CFU-C) were determined in vitro and under hypoxic conditions in vivo for 1 MeV fission neutrons and 300 kV X-rays. The obtained D0's were compared with previously observed D0's after irradiation in vivo under normal oxic conditions. With 1 MeV fission neutron irradiation no significant difference in radiosensitivity of the cell populations was observed between normal in vivo irradiation and in vitro irradiation. With 300 kV X-rays a lower radiosensitivity for all three cell populations was observed after in vitro compared to in vivo irradiation. In vivo irradiation with fission neutrons under hypoxic conditions led to a small decrease in radiosensitivity. The obtained oxygen enhancement ratio (OER) for fission neutrons varied from 1.2 for MRA[CFU-C] to 1.5 for CFU-C. After in vivo irradiation with 300 kV X-rays under hypoxic conditions much higher OERs were observed. An OER = 1.8 was obtained for CFU-S and for MRA[CFU-C] and for CFU-C OER 3.0 and 2.9 were observed. These results indicate that the radioresistance of primitive haemopietic stem cells (MRA[CFU-C]) compared to mature stem cells (CFU-S-7) is mainly due to intrinsic factors and not to differences in localization or oxygenation between primitive and mature stem cells.

Animals↗
PubMed1978

Granulocytic colonies on macrophage-coated membranes.

A macrophage cell coating covering a cellulose acetate disk was an effective microenvironment for the production of peroxidase-positive hematopoietic colonies. These developed after intraperitoneal injection of marrow cells with a linear cell relationship of dose to colonies formed. One colony formed for every 2,000 nucleated marrow cells injected. Observation of colony formation daily showed a steady increase in number and size until seven days after cell inoculation. X-irradiation (400 rads) eliminated intrinsic colony formation in BALB/c mice. Irradiation of the donor of the ip marrow cells resulted in a d0 of 95 rads. Treatment of the marrow donor with cytosine arabinoside had a suppressive effect on colony formation as did treatment of the host animal after receipt of the ip marrow. These results indicate that the precursor of the granulocytic colonies seen in the macrophage layers are more similar to committed granulocytic precursors than to the pluripotential stem cell.

Animals↗
PubMed1988

Transcriptional regulation of the leukocyte adherence protein beta subunit during human myeloid cell differentiation.

Adherence reactions involving human leukocytes are mediated by a family of glycoprotein surface antigens composed of three different alpha subunits designated alpha L, alpha M, and alpha X, each of which is associated with a single beta subunit in an alpha 1 beta 1 heterodimer structure. We cloned the cDNA for the common beta subunit and investigated beta subunit mRNA expression in HL-60 promyelocytic leukemia cells and human granulocytic cells. Leukocyte adherence receptor beta subunit mRNA transcripts were present in low levels in HL-60 myeloblasts and promyelocytes and increased 10-fold or greater with chemically induced differentiation to more mature granulocytes (using retinoic acid and dimethylformamide) or monocyte/macrophages (using phorbol myristate acetate). Levels of beta subunit mRNA expression were also increased both in normal human peripheral blood granulocytes and in granulocytes from patients with chronic myelogenous leukemia. Nuclear run-off assays indicated that the increased steady state level of the beta subunit mRNA in retinoic acid-differentiated HL-60 cells was secondary to enhanced beta subunit gene transcription. We conclude that mRNA levels for the beta subunit of the receptor on human leukocytes that mediates cellular adherence are increased in more mature granulocytic cells compared to immature myeloid precursors and that this enhanced mRNA expression is transcriptionally regulated.

CD18 Antigens↗
PubMed2004

Localization of serglycin in human neutrophil granulocytes and their precursors.

Serglycin is a major proteoglycan of hematopoietic cells. It is thought to play a role in the packaging of granule proteins in human neutrophil granulocytes. The presence of serglycin in myeloid cells has been demonstrated only at the transcriptional level. We generated a polyclonal antibody against recombinant human serglycin. Here, we show the localization of serglycin in humans during neutrophil differentiation. Immunocytochemistry revealed serglycin immunoreactivity in the Golgi area of promyelocytes (PM) and myelocytes (MC), as well as in a few band cells and mature neutrophil granulocytes. Granular staining was detected near the Golgi apparatus in some of the PM, and the major part of the cytoplasm was negative. Immunoelectron microscopy showed serglycin immunoreactivity located to the Golgi apparatus and a few immature granules of PM and MC. The decreasing level of serglycin protein during myeloid differentiation coincided with a decrease of mRNA expression, as evaluated by Northern blotting. Subcellular fractions of neutrophil granulocytes were obtained. Serglycin immunoreactivity was detected in the fraction containing Golgi apparatus, plasma membrane, and secretory vesicles by Western blotting and enzyme-linked immunosorbent assay. Serglycin was not detected in subcellular fractions containing primary, secondary, or tertiary granules. Together, these findings indicate that serglycin is located to the Golgi apparatus and a few immature granules during neutrophil differentiation. This is consistent with a function for serglycin in formation of granules in neutrophil granulocytes. Our findings contrast the view that native serglycin is present in mature granules and plays a role in packaging and regulating the activity of proteolytic enzymes there.

Blotting, Western↗
PubMed2006

Stage specific gene expression of serpins and their cognate proteases during myeloid differentiation.

Proteases and their serpin inhibitors are abundantly expressed in haemopoietic and peripheral blood cells. There is, however, relatively little information about the role played by serpins in the control of protease activity within these cells and in the pericellular region. The observation that mutations in the neutrophil elastase gene, which cause cyclic and severe congenital neutropenia, are associated with protease maldistribution gives some clue as to the potential importance of inhibitor proteins. To begin to address the role of protease/inhibitor balance in blood cells we used reverse transcription polymerase chain reaction to examine protease and serpin gene expression in mature peripheral blood cells, differentiating haemopoietic progenitors, leukaemic blasts and haemopoietic cell lines. The results demonstrate stage-specific expression of proteases together with widespread expression of intra- and extra-cellular serpins. The elastase inhibitors monocyte neutrophil elastase inhibitor (MNEI) and antitrypsin (AT) showed overlapping expression. MNEI is predominantly expressed in early haemopoietic progenitors while antitrypsin is mainly expressed in more mature myeloid precursors, peripheral blood granulocytes and mononuclear cells. Our results give an overall picture of serpin and protease gene expression and draws attention to the potential importance of elastase regulators at all stages of myelopoiesis.

Bone Marrow Cells↗
PubMed1987

Metabolic characterization of mouse bone marrow cells responsive to estrogenic inhibition: hexose monophosphate shunt enzyme activity in enriched populations of mature cells and progenitor cells.

Compounds with estrogenic activity cause initial toxic responses in the bone marrow characterized by hypocellularity and stem cell myelotoxicity. To elucidate the biochemical nature of these toxic responses, bone marrow cells were collected from mice treated with pharmacological doses of estrogenic chemicals, separated into enriched cell populations, and the enzymatic responses of the individual cell types characterized. Female B6C3F1 mice were injected s.c. with five daily doses of 0.07-5.6 mu moles diethylstilbestrol (DES) or 17-beta estradiol. At 4 days posttreatment body and organ weights were recorded and bone marrow was collected for enumeration and assay of stem cell proliferative responses and enzyme analyses. Treatment with higher dose levels of either estrogenic chemical caused equivalent thymic atrophy, but DES resulted in greater liver and spleen hypertrophy than estradiol. Hexose monophosphate shunt dehydrogenase enzymes in unfractionated bone marrow cells were more sensitive to inhibition by lower estrogen doses than representative enzymes from glycolysis of the Kreb's Cycle, and on an equimolar basis were inhibited to a greater extent by DES than by estradiol. Enzyme analyses after density gradient cell separation indicated that 70-80% of the hexose monophosphate shunt enzyme activity in bone marrow from untreated mice occurred in the enriched band of cells containing predominantly granulocyte-macrophages. The majority of the enzyme inhibition induced by DES treatment could also be ascribed to this cellular population. Furthermore, it was shown that DES had a greater inhibitory effect on the proliferative capacity of the committed stem cells than on the multipotential stem cell population, and the main response was again expressed in the enriched band of cells containing predominantly granulocyte-macrophage precursors. Preliminary endocrine ablation experiments indicated estrogen inhibition of hexose monophosphate shunt enzyme activity was independent of the adrenal and the ovary, but was mediated through the thymus at lower estrogen concentrations.

Adrenalectomy↗
PubMed2001

Circulating bone marrow osteoclast precursors and osteoclastogenesis in patients with type IIA and IIB hyperlipidemias.

Osteoclasts, the major source of calcium released during bone resorption, and their precursors preosteoclasts derive from bone marrow hemopoietic stem cells, granulocyte-macrophage colony-forming units. The factors responsible for commitment of colony-forming units into osteoclast precursors remain unknown. Studies of osteoclastogenesis in cultured blood mononuclear cells from patients with hyperlipidemia accompanied by atherosclerosis and calcification of vessels revealed high content of preosteoclasts in the blood.

Adult↗
PubMed1988

Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia.

The effects of recombinant interleukin-6 (IL-6) on the proliferation of blast precursors present in the peripheral blood of patients with acute myeloblastic leukemia (AML) was investigated. IL-6 had little effect by itself; however, it synergized with granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in the stimulation of AML blast colony formation. Responsiveness of blast progenitors to IL-6 was heterogeneous. On normal bone marrow cells the same synergy was observed on granulocyte and monocyte precursors (GM-CFC), while there was no significant effect on erythroid and multipotential precursors.

Cell Division↗
PubMed1992

Studies of bone marrow progenitor cells in lupus-prone mice. I. NZB marrow cells demonstrate increased growth in Whitlock-Witte culture and increased splenic colony-forming unit activity in the Thy-1-, lineage- population.

Previous studies have demonstrated that NZB marrow can transfer features of autoimmunity. Therefore, we undertook a study of NZB marrow to determine whether it demonstrated any phenotypic abnormalities. In Whitlock-Witte cultures, NZB marrow cells generated nonadherent cells at low seeding densities, densities at which marrow from other strains did not generate nonadherent cells. In contrast, NZB marrow grew less well than controls in Dexter cultures. Inasmuch as the latter favor growth of granulocyte-macrophage precursors and the former B cells, these results suggest a possible skewing of NZB marrow cells toward lymphocyte production. Unfractionated marrow cells from NZB mice were found to produce 10-fold more splenic colonies in lethally irradiated recipients than marrow cells from control mice. This result was independent of the genotype of the recipient. When the progenitor Thy-1lo, Lin- marrow subpopulation was studied, NZB mice did not differ substantially from controls regarding splenic CFU. Therefore, Thy-1-, Lin- marrow cells were studied as a possible source of the excess splenic CFU in NZB mice. Indeed, the NZB Thy-1-, Lin- population contained 30-fold more splenic CFU than did the Thy-1-, Lin- population from control mice. These results suggest that NZB mice have unusual marrow progenitor cells; such cells may play a role in their autoimmune disease.

Animals↗
PubMed1991

Analysis of leukotriene B4 metabolism in human promyelocytic HL-60 cells.

We previously reported that human alveolar macrophages rapidly metabolize the chemotactic active lipid mediator leukotriene B4 (LTB4) into the dihydro-LTB4 by reduction of one of the conjugated double bonds. We herein report that human HL-60 cells (a myeloid precursor which can be differentiated into granulocyte- as well as monocyte-like cells by dimethyl sulphoxide or phorbol myristate acetate) express a highly active LTB4 reductase in the undifferentiated state. Differentiation by dimethyl sulphoxide (1.3%) along the granulocyte lineage, as confirmed by light microscopy, conversion of NitroBlue Tetrazolium into formazan, failed to induce a substantial capacity for omega-oxidation of LTB4; this reaction is exclusively found in mature granulocytes. Studies with the cell homogenate of undifferentiated HL-60 cells indicated that the activity of the enzyme depends on the presence of NADPH, Ca2+ and Mg2+, with a pH optimum of 7.5 at 37 degrees C. The enzyme was not released into the supernatant after stimulation of HL-60 cells with phorbol myristate acetate (100 ng) or Ca2+ ionophore (7.5 microM). Subcellular fractionation revealed evidence that the LTB4 reductase is located within the membrane fraction. Purification of the enzyme by gel filtration and gel electrophoresis suggests an apparent molecular mass of 40 kDa.

Chromatography, Gel↗
PubMed1990

Role of IL-5 in IL-2-induced eosinophilia. In vivo and in vitro expression of IL-5 mRNA by IL-2.

We recently demonstrated in vivo that IL-5 was an important mediator of eosinophilia in mice with parasite infections. In this study, we examined whether or not IL-5 was actually responsible for the eosinophilia induced by injection of human rIL-2. Mice administered hIL-2 developed eosinophilia during the course of the series of injections. This eosinophilia could be suppressed by a single injection of mAb against murine IL-5. The number of eosinophilic precursors increased more in the spleen cells of the IL-2-treated mice in comparison to the control mice, although in bone marrow precursors showed little change. Similarly, the number of granulocytic precursors increased markedly in the spleen cells of IL-2-treated mice. In vitro polymerase chain reaction amplification of cDNA subfragments corresponding to IL-5 mRNA (reverse transcription-polymerase chain reaction), followed by Southern blot analysis, revealed enhancement of IL-5 mRNA expression in spleen cells 3 days after starting the human IL-2 injections. We also observed enhanced murine IL-5 mRNA expression in spleen cells stimulated with IL-2 in vitro. The level of murine IL-5 mRNA expression by IL-2-stimulated spleen cells from normal mice increased at 24 h, reached a plateau after 48 h, and decreased again within 72 h of starting culture. These results indicate that the eosinophilia induced by IL-2 in vivo is presumably mediated by IL-5 released from IL-2-stimulated lymphocytes.

Animals↗
PubMed1986

Cytogenetic evidence for partially committed myeloid progenitor cell origin of chronic myelomonocytic leukaemia and juvenile chronic myeloid leukaemia: both granulocyte-macrophage precursors and erythroid precursors carry identical marker chromosome.

We used a micromethod for cytogenetic analysis from single haematopoietic colonies to study two adults with chronic myelomonocytic leukaemia (CMML) and a boy with juvenile chronic myeloid leukaemia (JCML) carrying distinct chromosome abnormalities, 7q-, der(21), and trisomy 21. We wanted to know if both granulocyte-macrophage (GM) and erythroid precursors are involved in the abnormal clone. In all three patients, their chromosome abnormality was seen in almost all metaphases obtained from GM-colonies and erythroid bursts. Peripheral blood leucocytes stimulated with phytohaemagglutinin exhibited only normal karyotypes. Clones of B-cell produced by Epstein-Barr virus had only normal karyotypes in the CMML patients. These findings indicate that CMML and JCML are clonal haemopathies that originate in a partially committed myeloid progenitor cell.

Aged↗
PubMed1983

Peripheral blood cells in the study of chromosome aberrations of patients with chronic myeloid leukaemia or myelofibrosis.

Chromosome studies were performed on peripheral blood (PB) cells with and without stimulation, and/or on bone marrow (BM) cells from 21 patients with chronic myeloid leukaemia (CML), and 18 patients with myelofibrosis (MF). Our results show that almost all the patients with immature granulocyte precursors in PB also had mitotic cells in their unstimulated PB. In CML all unstimulated mitoses had the Philadelphia chromosome. In each patient the abnormal karyotype in the PB was the same as in the BM. Because of the high frequency of dry taps in myelofibrosis, the tissue of choice for chromosome study is peripheral blood.

Blood Cells↗