scholarly journals Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2007-2013 ◽  
Author(s):  
C Denzlinger ◽  
W Tetzloff ◽  
HH Gerhartz ◽  
R Pokorny ◽  
S Sagebiel ◽  
...  
Keyword(s):  
Chinese Hamster ◽  
Pharmacokinetic Parameters ◽  
Colony Stimulating Factor ◽  
Drug Induced ◽  
E Coli ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM- CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.

scholarly journals Differential activation of the endogenous leukotriene biosynthesis by two different preparations of granulocyte-macrophage colony-stimulating factor in healthy volunteers

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2007-2013 ◽  
Author(s):  
C Denzlinger ◽  
W Tetzloff ◽  
HH Gerhartz ◽  
R Pokorny ◽  
S Sagebiel ◽  
...  
Keyword(s):  
Chinese Hamster ◽  
Pharmacokinetic Parameters ◽  
Colony Stimulating Factor ◽  
Drug Induced ◽  
E Coli ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Results from in vitro investigations and recent data obtained in patients with drug-induced cytopenia or myelodysplasia suggest that leukotrienes may be involved in mediating some of the actions of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the present study, the possible role of leukotrienes was further characterized in 21 healthy individuals to avoid modification of response to GM-CSF by disease-specific variables. The effects of two different preparations of human recombinant GM-CSF, ie, glycosylated GM- CSF as expressed in a Chinese hamster ovary carcinoma (CHO) cell line and nonglycosylated GM-CSF obtained from Escherichia coli, were compared. GM-CSF was administered subcutaneously at a single dose of 0.7 nmol/kg body weight. Pharmacokinetic parameters and hematopoietic and adverse effects were monitored by blood analyses or physical examination, respectively. Leukotriene generation in vivo was evaluated by determination of leukotriene E4 and N-acetyl-leukotriene E4 in urine. After the injection of GM-CSF from E coli, serum concentrations increased and decreased more rapidly and reached a 2.3-fold higher maximum compared with GM-CSF from CHO. GM-CSF induced a biphasic change in leukocyte counts that proceeded considerably faster after the E coli preparation than after GM-CSF from CHO. The urinary leukotriene concentration increased 1.3- to 14-fold or 2.1- to 44-fold after the administration of GM-CSF from CHO or E coli, respectively. Urinary leukotriene concentrations correlated significantly with the maximum of basophil counts and correlated with the occurrence of some adverse reactions, ie, flu-like symptoms, bone pain, or dyspnoea. Our data confirm the conception that leukotrienes may play a significant role in GM-CSF action in vivo. They especially direct attention to the possible relevance of leukotrienes to untoward effects of GM-CSF treatment.

scholarly journals Hematopoietic and Lymphopoietic Responses in Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF ) Receptor Transgenic Mice Injected With Human GM-CSF

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1031-1038 ◽  
Author(s):  
I. Nishijima ◽  
T. Nakahata ◽  
S. Watanabe ◽  
K. Tsuji ◽  
I. Tanaka ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Blood Cells ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Dose Dependent ◽  
Stimulating Factor

Abstract Using a clonal assay of bone marrow (BM) cells from transgenic mice (Tg-mice) expressing the human granulocyte-macrophage colony-stimulating factor receptor (hGM-CSFR), we found in earlier studies that hGM-CSF alone supported the development not only of granulocyte-macrophage colonies, but also of erythrocytes, megakaryocytes, mast cells, blast cells, and mixed hematopoietic colonies. In this report, we evaluated the in vivo effects of hGM-CSF on hematopoietic and lymphopoietic responses in the hGM-CSFR Tg-mice. Administration of this factor to Tg-mice resulted in dose-dependent increases in numbers of reticulocytes and white blood cells (WBCs) in the peripheral blood. Morphological analysis of WBCs showed that the numbers of all types of the cell, including neutrophils, eosinophils, monocytes, and lymphocytes increased; the most remarkable being in lymphocytes that contained a number of large granular lymphocytes (LGLs) in addition to mature T and B cells. However, total cellularity of the BM of the Tg-mice decreased in a dose-dependent manner when hGM-CSF was injected. In sharp contrast to the BM, spleens of the Tg-mice were grossly enlarged. Although all types of blood cells and hematopoietic progenitors increased in the spleen, erythroid cells and their progenitors showed the most significant increase. Increased numbers of megakaryocytes and LGLs were also observed in spleen and liver of the treated Tg-mice. Flow cytometric analysis showed that LGLs expanded in Tg-mice expressed Mac-1+CD3−NK1.1+. The thymus of Tg-mice treated with hGM-CSF exhibited a dose-dependent shrinkage and a remarkable decrease in CD4+CD8+ cells. Thus, hGM-CSF stimulated not only myelopoiesis but also erythropoiesis and megakaryopoiesis of hGM-CSFR Tg-mice in vivo, in accordance with our reported in vitro findings. In addition, hGM-CSF affected the development of lymphoid cells, including natural killer cells of these Tg-mice.

Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte-macrophage colony-stimulating factor and interleukin 3

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2603-2605 ◽  
Author(s):  
Armin G. Jegalian ◽  
Adriana Acurio ◽  
Glenn Dranoff ◽  
Hong Wu
Keyword(s):  
Erythropoietin Receptor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Definitive Erythropoiesis ◽  
Stimulating Factor

Erythropoietin (EPO) and its receptor (EPOR) are critical for definitive erythropoiesis, as mice lacking either gene product die during embryogenesis with severe anemia. Here we demonstrate that mice expressing just one functional allele of the EpoR have lower hematocrits and die more frequently than do wild-type littermates on anemia induction. Furthermore, EpoR+/−erythroid colony-forming unit (CFU-E) progenitors are reduced both in frequency and in responsiveness to EPO stimulation. To evaluate the interaction between EPO and granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL-3),GM-CSF−/− orIL-3−/− mice were interbred withEpoR+/− mice. Deletion of either GM-CSF or IL-3 also leads to reduction in CFU-E numbers and hematocrits but does not significantly alter steady-state erythroid burst-forming unit numbers. These results suggest EpoR haploinsufficiency and promotion of in vivo erythropoiesis by GM-CSF and IL-3.

scholarly journals A Two-Hit Mechanism for Vitamin D3-Mediated Transcriptional Repression of the Granulocyte-Macrophage Colony-Stimulating Factor Gene: Vitamin D Receptor Competes for DNA Binding with NFAT1 and Stabilizes c-Jun

1999 ◽  
Vol 19 (6) ◽  
pp. 4191-4199 ◽  
Author(s):  
Terri L. Towers ◽  
Teodora P. Staeva ◽  
Leonard P. Freedman
Keyword(s):  
Vitamin D ◽  
Dna Binding ◽  
Transcriptional Repression ◽  
Inhibitory Effect ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT We previously described a control element in the granulocyte-macrophage colony-stimulating factor (GM-CSF) enhancer that is necessary and sufficient to mediate both transcriptional activation in response to T-cell stimuli and transcriptional repression by 1,25-dihydroxyvitamin D3[1,25(OH)2D3] through the vitamin D3 receptor (VDR). This DNA element is a composite site that is recognized by both Fos-Jun and NFAT1; it is directly bound by VDR in the absence of a retinoid X receptor as an apparent monomer, and it is bound in a unique tertiary conformation. We describe here the mechanism by which VDR elicits its transcriptional inhibitory effect. Firstly, VDR outcompetes NFAT1 for binding to the composite site. Overexpression of NFAT1 in vivo by transient transfection is able to relieve the 1,25(OH)2D3-dependent repression. Secondly, VDR stabilizes the binding of a Jun-Fos heterodimer to the adjacent AP-1 portion of the element. This appears to occur through a direct interaction between VDR and c-Jun, as demonstrated in vitro by direct glutathione S-transferase coprecipitation assays. In vivo, overexpression of c-Jun, but not c-Fos, leads to a rescue of the 1,25(OH)2D3-mediated repression. Transfected FLAG-VDR bound to the NFAT1–AP-1 DNA binding element can be selectively precipitated from nuclear extracts that are made from cells treated with activating agents in the presence of 1,25(OH)2D3. VDR is not detected in the complex in the absence of the ligand. Thus, VDR acts selectively on the two components required for activation of this promoter/enhancer: it competes with NFAT1 for binding to the composite site, positioning itself adjacent to Jun-Fos on the DNA. Co-occupancy apparently leads to an inhibitory effect on c-Jun’s transactivation function. These two events mediated by VDR effectively block the NFAT1–AP-1 activation complex, resulting in an attenuation of activated GM-CSF transcription.

scholarly journals Hematopoietic and Lymphopoietic Responses in Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF ) Receptor Transgenic Mice Injected With Human GM-CSF

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1031-1038 ◽  
Author(s):  
I. Nishijima ◽  
T. Nakahata ◽  
S. Watanabe ◽  
K. Tsuji ◽  
I. Tanaka ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Blood Cells ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Dose Dependent ◽  
Stimulating Factor

Using a clonal assay of bone marrow (BM) cells from transgenic mice (Tg-mice) expressing the human granulocyte-macrophage colony-stimulating factor receptor (hGM-CSFR), we found in earlier studies that hGM-CSF alone supported the development not only of granulocyte-macrophage colonies, but also of erythrocytes, megakaryocytes, mast cells, blast cells, and mixed hematopoietic colonies. In this report, we evaluated the in vivo effects of hGM-CSF on hematopoietic and lymphopoietic responses in the hGM-CSFR Tg-mice. Administration of this factor to Tg-mice resulted in dose-dependent increases in numbers of reticulocytes and white blood cells (WBCs) in the peripheral blood. Morphological analysis of WBCs showed that the numbers of all types of the cell, including neutrophils, eosinophils, monocytes, and lymphocytes increased; the most remarkable being in lymphocytes that contained a number of large granular lymphocytes (LGLs) in addition to mature T and B cells. However, total cellularity of the BM of the Tg-mice decreased in a dose-dependent manner when hGM-CSF was injected. In sharp contrast to the BM, spleens of the Tg-mice were grossly enlarged. Although all types of blood cells and hematopoietic progenitors increased in the spleen, erythroid cells and their progenitors showed the most significant increase. Increased numbers of megakaryocytes and LGLs were also observed in spleen and liver of the treated Tg-mice. Flow cytometric analysis showed that LGLs expanded in Tg-mice expressed Mac-1+CD3−NK1.1+. The thymus of Tg-mice treated with hGM-CSF exhibited a dose-dependent shrinkage and a remarkable decrease in CD4+CD8+ cells. Thus, hGM-CSF stimulated not only myelopoiesis but also erythropoiesis and megakaryopoiesis of hGM-CSFR Tg-mice in vivo, in accordance with our reported in vitro findings. In addition, hGM-CSF affected the development of lymphoid cells, including natural killer cells of these Tg-mice.

scholarly journals Effect of recombinant granulocyte-macrophage colony-stimulating factor on murine thrombocytopoiesis in vitro and in vivo

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1433-1438
Author(s):  
T Ishibashi ◽  
H Kimura ◽  
Y Shikama ◽  
T Uchida ◽  
S Kariyone ◽  
...  
Keyword(s):  
Tritiated Thymidine ◽  
In Vivo Studies ◽  
Colony Stimulating Factor ◽  
Serum Free ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

To investigate the effect of recombinant granulocyte-macrophage colony- stimulating factor (rGM-CSF) on murine megakaryocytopoiesis in vitro, the factor was added to both serum-free colony assays and liquid marrow cultures. GM-CSF had a significant megakaryocytic colony-stimulating activity. After 2 hours of preincubation with and without 10 ng/mL rGM- CSF, the percentage of megakaryocyte colony-forming cell (CFU-MK) in DNA synthesis was determined by tritiated-thymidine suicide using colony growth. The reduction of CFU-MK colony numbers in marrow culture was 47.5% +/- 9.9%, 20.9% +/- 5.2% (control), respectively, indicating that the factor affected cell cycle at CFU-MK levels. When acetylcholinesterase (AchE) production was measured fluorometrically after 4 days of liquid culture, rGM-CSF elicited an increase in AchE activity in a dose-dependent fashion. To determine if the hematopoietin acts directly on megakaryocytic differentiation, 2 ng/mL rGM-CSF was added to serum-free cultures of 295 single megakaryocytes isolated from CFU-MK colonies. An increase in size was observed in 65% of cells initially 10 to 20 microns in diameter, 71% of cells 20 to 30 microns, and 40% of cells greater than 30 microns. Conversely, in absence of GM- CSF, 17%, 31%, and 10% of cells in each group increased in diameter. These data suggest that rGM-CSF promotes murine megakaryocytopoiesis in vitro and that the response to the factor is direct. To determine if the factor influences megakaryocytic/thrombocytic lineage in vivo, 1 and 5 micrograms of rGM-CSF were administered intraperitoneally every 12 hours for 6 consecutive days. Although a two- to three-fold increase in peripheral granulocytes was observed, neither megakaryocytic progenitor cells or platelets changed. Histologic analysis of bone marrow megakaryocytes showed no increase in size and number. The in vivo studies demonstrated no effect of GM-CSF on thrombocytopoiesis. The discrepancies between the in vitro and in vivo effects of GM-CSF require additional investigations.

scholarly journals Granulocyte-macrophage colony-stimulating factor-induced antibody- dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3474-3479 ◽  
Author(s):  
BS Charak ◽  
R Agah ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Cellular Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce antitumor activity in peripheral blood monocytes. We examined the role of GM-CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT) setting. GM- CSF induced a potent ADCC in BM macrophages against a murine melanoma in vitro. Treatment with GM-CSF alone or with antibody alone had no effect, whereas therapy with combination of both these agents resulted in a significant reduction in dissemination of melanoma both in a nontransplant as well as in BMT settings, with results being more optimal in the latter setting. Adoptive transfer of BM macrophages harvested from mice undergoing therapy with GM-CSF plus antibody significantly reduced the dissemination of melanoma in secondary recipients but only after irradiation, not in intact mice. GM-CSF also induced significant ADCC in human BM macrophages against a melanoma and a lymphoma in vitro and against a lymphoma implanted in nude mice in vivo. Again, these effects were more optimal after chemotherapy. These data suggest that treatment with GM-CSF plus tumor-specific monoclonal antibodies after BMT may induce an antitumor effect and help eradicate the minimal residual disease.

Sign in / Sign up

Export Citation Format

Share Document