Induction of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Granulocyte Colony-Stimulating Factor (G-CSF) Expression in Bone Marrow and Fractionated Marrow Cell Populations by Interleukin 3 (IL-3): IL-3-Mediated Positive Feedback Mechanisms of Granulopoiesis

1994 ◽  
Vol 11 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Takashi Tsuji ◽  
Kenkichi Sugimoto ◽  
Takanori Yanai ◽  
Emi Takashita ◽  
Kazuhiro J. Mori
Keyword(s):  
Bone Marrow ◽  
Marrow Cell ◽  
Cell Populations ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Feedback Mechanisms ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Stimulation of nonclonal hematopoiesis and suppression of the neoplastic clone after treatment with recombinant human granulocyte- macrophage colony-stimulating factor in a patient with therapy-related myelodysplastic syndrome

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1491-1498 ◽  
Author(s):  
S Vadhan-Raj ◽  
HE Broxmeyer ◽  
G Spitzer ◽  
A LeMaistre ◽  
S Hultman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Fragment Length Polymorphism ◽  
Marrow Cell ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Selective Growth Advantage ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract A complete hematologic remission was achieved in a patient with therapy- related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony- stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism- methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

scholarly journals Stimulation of nonclonal hematopoiesis and suppression of the neoplastic clone after treatment with recombinant human granulocyte- macrophage colony-stimulating factor in a patient with therapy-related myelodysplastic syndrome

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1491-1498 ◽  
Author(s):  
S Vadhan-Raj ◽  
HE Broxmeyer ◽  
G Spitzer ◽  
A LeMaistre ◽  
S Hultman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Fragment Length Polymorphism ◽  
Marrow Cell ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Selective Growth Advantage ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

A complete hematologic remission was achieved in a patient with therapy- related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony- stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism- methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

scholarly journals Quantitative cell-cycle progression analysis of the first three successive cell cycles of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor-stimulated human CD34+ bone marrow cells in relation to their colony formation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3211-3216 ◽  
Author(s):  
F Lardon ◽  
DR Van Bockstaele ◽  
HW Snoeck ◽  
ME Peetermans
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Target Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cell Cycles ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The bromodeoxyuridine (BrdU)-Hoechst flow cytometric technique was applied to study the immediate cell kinetic response of highly purified human (h) bone marrow progenitor cells (CD(34+)-sorted fraction) to h granulocyte colony-stimulating factor (G-CSF) and/or h granulocyte- macrophage colony-stimulating factor (GM-CSF). The technique permits us to differentiate cycling from noncycling cells and to make a quantitative assessment of cell cycles after stimulation. Semisolid agar and single-cell liquid cultures were also performed to compare these initial events to the effects observed after 14 days of culture. The combination of G-CSF plus GM-CSF, acting synergistically in day 14 cultures, was found to have a subadditive effect in the first cell cycles, thereby indicating partial overlap of the different target cells. However, this combination accelerated transit through the cell cycle, as could be seen from the higher number of cells in the third cell cycle after 72 hours of stimulation. We conclude that, apart from the unresponsive cells, the CD34+ compartment consists of cells responsive to both G-CSF and GM-CSF, and cells responsive to either one of the CSFs alone, and that the combination of the two CSFs speeds up the cell cycle traverse rate for a significant fraction of the target cells that are initially responsive for both G-CSF and GM-CSF. The latter supports the hypothesis of an overlapping signalling pathway of G-CSF and GM-CSF.

scholarly journals Quantitative cell-cycle progression analysis of the first three successive cell cycles of granulocyte colony-stimulating factor and/or granulocyte-macrophage colony-stimulating factor-stimulated human CD34+ bone marrow cells in relation to their colony formation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3211-3216
Author(s):  
F Lardon ◽  
DR Van Bockstaele ◽  
HW Snoeck ◽  
ME Peetermans
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Target Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cell Cycles ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The bromodeoxyuridine (BrdU)-Hoechst flow cytometric technique was applied to study the immediate cell kinetic response of highly purified human (h) bone marrow progenitor cells (CD(34+)-sorted fraction) to h granulocyte colony-stimulating factor (G-CSF) and/or h granulocyte- macrophage colony-stimulating factor (GM-CSF). The technique permits us to differentiate cycling from noncycling cells and to make a quantitative assessment of cell cycles after stimulation. Semisolid agar and single-cell liquid cultures were also performed to compare these initial events to the effects observed after 14 days of culture. The combination of G-CSF plus GM-CSF, acting synergistically in day 14 cultures, was found to have a subadditive effect in the first cell cycles, thereby indicating partial overlap of the different target cells. However, this combination accelerated transit through the cell cycle, as could be seen from the higher number of cells in the third cell cycle after 72 hours of stimulation. We conclude that, apart from the unresponsive cells, the CD34+ compartment consists of cells responsive to both G-CSF and GM-CSF, and cells responsive to either one of the CSFs alone, and that the combination of the two CSFs speeds up the cell cycle traverse rate for a significant fraction of the target cells that are initially responsive for both G-CSF and GM-CSF. The latter supports the hypothesis of an overlapping signalling pathway of G-CSF and GM-CSF.

scholarly journals Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation

2008 ◽  
Vol 295 (1) ◽  
pp. L114-L122 ◽  
Author(s):  
Megan N. Ballinger ◽  
Leah L. N. Hubbard ◽  
Tracy R. McMillan ◽  
Galen B. Toews ◽  
Marc Peters-Golden ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Host Defense ◽  
Receptor Expression ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Bacterial Killing ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E2(PGE2) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF−/− donors (GM-CSF−/− BMT) with untransplanted mice. GM-CSF−/− BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF−/− BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF−/− BMT mice overproduced PGE2, but expression of the inhibitory EP2receptor was diminished. As a consequence of decreased EP2receptor expression, we found diminished accumulation of cAMP in response to PGE2stimulation in GM-CSF−/− BMT AMs compared with control BMT AMs. In addition, GM-CSF−/− BMT AMs retained cysteinyl leukotriene production and normal TNF-α response compared with AMs from control BMT mice. GM-CSF−/− BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF−/− recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.

scholarly journals Heparin inhibits the expression of interleukin-11 and granulocyte- macrophage colony-stimulating factor in primate bone marrow stromal fibroblasts through mRNA destabilization

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2526-2533 ◽  
Author(s):  
L Yang ◽  
YC Yang
Keyword(s):  
Bone Marrow ◽  
Extracellular Matrix ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Extracellular Matrix Components ◽  
Macrophage Colony Stimulating Factor ◽  
Mrna Destabilization ◽  
Matrix Components ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Interactions between different cytokines, extracellular matrix components, and various cell types inside the bone marrow microenvironment are believed to play important roles in the regulation of hematopoiesis. We observed that both interleukin-1 (IL-1) and 12-O- tetradecanoylphorbol-13-acetate (TPA) can stimulate the expression of IL-11 and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in a primate bone marrow stromal fibroblast cell line, PU-34. We also found that IL-1 or TPA-stimulated IL-11 and GM-CSF expression in PU-34 cells can be abolished by heparin, a class of molecules related to extracellular matrix components, glycosaminoglycans. Because the growth inhibitory signals provided by extracellular factors were less understood, the mechanisms of heparin inhibition of IL-11 and GM-CSF gene expression were further investigated. Our data demonstrate for the first time that heparin did not alter the transcription of endogenous IL-11 and GM-CSF genes or an exogenous IL-11 promoter construct containing an AP-1 sequence. Instead, heparin facilitated the degradation of the corresponding mRNAs. Through RNA gel shift assays, heparin-mediated mRNA destabilization was tentatively linked to its competition for mRNA binding proteins both in the cell-free system and in intact cells. Collectively, our findings suggest that varying degrees of heparin inhibition may provide a novel mechanism for the regulation of cytokine expression during the growth and differentiation of different lineages of hematopoietic cells.

Granulocyte-macrophage colony-stimulating factor increases l-arginine transport through the induction of CAT2 in bone marrow-derived macrophages

2006 ◽  
Vol 290 (5) ◽  
pp. C1364-C1372 ◽  
Author(s):  
Lorena Martín ◽  
Mónica Comalada ◽  
Luc Marti ◽  
Ellen I. Closs ◽  
Carol L. MacLeod ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Amino Acid ◽  
Alternative Activation ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Arginine Transport ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Arginase I

l-Arginine transport is crucial for macrophage activation because it supplies substrate for the key enzymes nitric oxide synthase 2 and arginase I. These enzymes participate in classic and alternative activation of macrophages, respectively. Classic activation of macrophages is induced by type I cytokines, and alternative activation is induced by type II cytokines. The granulocyte macrophage colony-stimulating factor (GM-CSF), in addition to inducing proliferation and differentiation of macrophages, activates arginase I, but its action on l-arginine transport is unknown. We studied the l-arginine transporters that are active in mouse primary bone marrow-derived macrophages (BMM) and examined the effect of GM-CSF treatment on transport activities. Under basal conditions, l-arginine entered mainly through system y+L (>75%). The remaining transport was explained by system y+ (<10%) and a diffusion component (10–15%). In response to GM-CSF treatment, transport activity increased mostly through system y+ (>10-fold), accounting for about 40% of the total l-arginine transport. The increase in y+ activity correlated with a rise in cationic amino acid transporter (CAT)-2 mRNA and protein. Furthermore, GM-CSF induced an increase in arginase activity and in the conversion of l-arginine to ornithine, citrulline, glutamate, proline, and polyamines. BMM obtained from CAT2-knockout mice responded to GM-CSF by increasing arginase activity and the expression of CAT1 mRNA, which also encodes system y+ activity. Nonetheless, the increase in CAT1 activity only partially compensated the lack of CAT2 and l-arginine metabolism was hardly stimulated. We conclude that BMM present mainly y+L activity and that, in response to GM-CSF, l-arginine transport augments through CAT2, thereby increasing the availability of this amino acid to the cell.

Randomized Cross-Over Trial of Progenitor-Cell Mobilization: High-Dose Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor (G-CSF) Versus Granulocyte-Macrophage Colony-Stimulating Factor Plus G-CSF

2000 ◽  
Vol 18 (9) ◽  
pp. 1824-1830 ◽  
Author(s):  
Omer N. Koç ◽  
Stanton L. Gerson ◽  
Brenda W. Cooper ◽  
Mary Laughlin ◽  
Howard Meyerson ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens seems to vary considerably, making comparison between regimens difficult. To eliminate this inter-patient variability, we designed a cross-over trial and prospectively compared the number of progenitors mobilized into blood after granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C) in the same patient. PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses. After a washout period, patients were then crossed over to the alternate regimen (C2 and G2, respectively) and underwent two additional leukaphereses. The hematopoietic progenitor-cell content of each collection was determined. In addition, toxicity and charges were tracked. RESULTS: Regimen C (n = 50) resulted in mobilization of more CD34+ cells (2.7-fold/kg/apheresis), erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units–granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to the same patients (n = 46; paired t test, P < .01 for all comparisons). Compared with regimen G, regimen C resulted in better mobilization, whether it was given first (P = .025) or second (P = .02). The ability to achieve a target collection of ≥ 2 × 106 CD34+ cells/kg using two leukaphereses was 50% after G1 and 90% after C1. Three of the seven patients in whom mobilization was poor after G1 had ≥ 2 × 106 CD34+ cells/kg with two leukaphereses after C2. In contrast, when regimen G was given second (G2), seven out of 10 patients failed to achieve the target CD34+ cell dose despite adequate collections after C1. Thirty percent of the patients (nine of 29) given regimen C were admitted to the hospital because of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The higher cost of regimen C was balanced by higher CD34+ cell yield, resulting in equivalent charges based on cost per CD34+ cell collected. CONCLUSION: We report the first clinical trial that used a cross-over design showing that high-dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then GM-CSF plus G-CSF when tested in the same patient regardless of sequence of administration, although the regimen is associated with greater morbidity. Patients who fail to achieve adequate mobilization after regimen G can be treated with regimen C as an effective salvage regimen, whereas patients who fail regimen C are unlikely to benefit from subsequent treatment with regimen G. The cross-over design allowed detection of significant differences between regimens in a small cohort of patients and should be considered in design of future comparisons of mobilization regimens.

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