scholarly journals Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3264-3270 ◽  
Author(s):  
C Dubois ◽  
MH Schlageter ◽  
A de Gentile ◽  
F Guidez ◽  
N Balitrand ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Interleukin 1 ◽  
Leukemic Cells ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Stimulating Factor

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte- macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all- trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.

scholarly journals Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3264-3270 ◽  
Author(s):  
C Dubois ◽  
MH Schlageter ◽  
A de Gentile ◽  
F Guidez ◽  
N Balitrand ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Interleukin 1 ◽  
Leukemic Cells ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Stimulating Factor

Abstract Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte- macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all- trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.

scholarly journals Functional NF-IL6/CCAAT enhancer-binding protein is required for tumor necrosis factor alpha-inducible expression of the granulocyte colony-stimulating factor (CSF), but not the granulocyte/macrophage CSF or interleukin 6 gene in human fibroblasts.

1995 ◽  
Vol 181 (2) ◽  
pp. 793-798 ◽  
Author(s):  
M Kiehntopf ◽  
F Herrmann ◽  
M A Brach
Keyword(s):  
Tumor Necrosis ◽  
Human Fibroblasts ◽  
Transient Transfection ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Stimulating Factor ◽  
Necrosis Factor

Tumor necrosis factor (TNF) alpha participates in the regulation of the acute-phase, immune, and inflammatory responses. Target genes known to be transcriptionally activated by TNF-alpha include the granulocyte (G)-colony-stimulating factor (CSF) gene, the granulocyte/macrophage (GM)-CSF gene, as well as the interleukin (IL) 6 gene. Functional nuclear factor (NF)-IL6 recognition sites have been identified in regulatory regions of these genes by transient transfection studies using deleted promoter constructs. In addition, NF-IL6 is known to form heterodimeric complexes with the NF-kappa B transcription factor, which is also engaged in the transcriptional regulation of these genes. The indispensable importance of NF-IL6 for regulating gene expression of proinflammatory cytokine genes in response to inflammatory stimuli in vivo remains, however, unclear. We here report, by using both antisense (AS) oligodesoxyribonucleotide (ODN) and ribozyme (RZ)-mediated specific elimination of NF-IL6 transcripts in human fibroblasts, that TNF-alpha-induced synthesis of G-CSF, but not of GM-CSF or IL-6, is abolished in the absence of functional NF-IL6 in vivo. Both AS ODN and RZ targeting of the NF-IL6 transcript eliminate NF-IL6 protein, as shown in Western blot analysis and electrophoretic mobility shift assays. Similarly, fibroblasts exposed to either the AS NF-IL6 ODN or the NF-IL6 RZ, but not to the sense or nonsense ODN or a mutated ribozyme, also failed to respond with functional activation of NF-IL6 as assayed in transient transfection studies using heterologous promoter constructs harboring the NF-IL6 recognition site. In contrast, protein synthesis, DNA-binding activity, and transcriptional activation capacity of the NF-kappa B transcription factor is not impaired upon exposure to either ODN or RZ. Fibroblasts that had been cultured in the presence of the AS NF-IL6 ODN or the NF-IL6RZ failed to synthesize G-CSF protein in response to TNF-alpha, while TNF-alpha-inducible transcription and release of GM-CSF and IL-6 was preserved.

scholarly journals Interactions of granulocyte-macrophage colony-stimulating factor (CSF), granulocyte CSF, and tumor necrosis factor alpha in the priming of the neutrophil respiratory burst

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 745-753 ◽  
Author(s):  
A Khwaja ◽  
JE Carver ◽  
DC Linch
Keyword(s):  
Respiratory Burst ◽  
Ex Vivo ◽  
Tnf Alpha ◽  
H2o2 Production ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Stimulating Factor

Abstract Exposure of neutrophils to a range of cytokines augments their response to subsequent agonist-induced activation of the respiratory burst. We have examined the effects of several of these factors, both singly and in combination, on the priming of f-met-leu-phe (FMLP) and complement C5a-stimulated neutrophil H2O2 production, using a whole blood flow cytometric assay designed to minimize artefactual activation. Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF alpha) produced a similar degree of priming of the FMLP-stimulated burst in vitro (558% +/- 86%, n = 41, and 581% +/- 95%, n = 21, of the response seen with FMLP alone, respectively), but with markedly different kinetics (half-maximal response 20 minutes and 7 minutes, respectively). Preincubation with granulocyte colony- stimulating factor (G-CSF) alone caused only modest priming (202% +/- 39%, n = 14). Priming with cytokine combinations of the FMLP-stimulated burst showed that the combinations of G-CSF and TNF alpha and GM-CSF and TNF alpha are highly synergistic, with recruitment of neutrophils unresponsive to priming by single agents. Priming with the combination of GM-CSF and G-CSF was not significantly different to priming with GM- CSF alone. Similar results were obtained using C5a as the respiratory burst stimulus. Significant priming of the FMLP-stimulated respiratory burst was seen in vivo in patients receiving an infusion of GM-CSF (332% +/- 50% of preinfusion response to FMLP, P less than .005, n = 8). Priming was also seen in patients receiving G-CSF (152% +/- 58%, n = 5), although this did not reach conventional significance levels (.05 less than P less than .1). Although GM-CSF infusion caused priming in vivo, this was 48% less than predicted by preinfusion in vitro responses. This result was not due to inadequate GM-CSF levels as addition of further GM-CSF ex vivo did not correct the response. However, these neutrophils were still able to respond appropriately to ex vivo priming with TNF alpha, with a doubling in H2O2 production.

In vivo administration of granulocyte colony-stimulating factor (G- CSF), granulocyte-macrophage CSF, interleukin-1 (IL-1), and IL-4, alone and in combination, after allogeneic murine hematopoietic stem cell transplantation

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1376-1382 ◽  
Author(s):  
K Atkinson ◽  
C Matias ◽  
A Guiffre ◽  
R Seymour ◽  
M Cooley ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Control Value ◽  
Effective Combination ◽  
Stimulating Factor ◽  
Factor G

Abstract BALB/c mice (H-2d) given 10 Gy total body irradiation (TBI) followed by 10(7) bone marrow (BM) and 10(6) spleen cells from C57BL/6 (H-2b) donor mice received recombinant cytokines intraperitoneally (IP) twice daily. The effect on neutrophil recovery rate, graft-v-host disease (GVHD), and survival was assessed. Four reagents were used: granulocyte-colony- stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-1 (IL-1) and IL-4, both alone and in combination. The most effective combination for increasing the circulating absolute neutrophil account (ANC) above the control value at day 7 posttransplant was the combination of G-CSF and IL-1 (mean ANC 2.4 +/- 1.6 x 10(9)/L as compared with control value of 0.07 +/- 0.05, P less than .02), followed by G-CSF alone (mean ANC 1.1 +/- 0.2, P less than .0001), the combination of GM-CSF plus IL-1 (mean ANC 0.8 +/- 0.3, P less than .002), and the combination of G-CSF plus GM-CSF (mean ANC 0.8 +/- 0.3, p less than .005). At day 10 posttransplant, the most effective combination in raising the ANC was the combination of G-CSF plus GM-CSF (mean ANC 7.5 +/- 2.3 as compared with control value of 3.5 +/- 1.1, P less than .01), followed by G-CSF alone (mean ANC 6.9 +/- 2.1, P less than .02). At the doses used, neither G-CSF nor GM-CSF had a deleterious effect on the incidence or severity of GVHD; indeed, GM- CSF was associated with improved survival. In contrast, IL-1 at doses greater than or equal to 100 ng twice daily caused marked early mortality, and there was a suggestion that IL-4 at doses of 500 ng twice daily resulted in increased late mortality, possibly owing to exacerbation of GVHD. This model appears to be of value for exploring the use of hematopoietic growth factors before they are used clinically in marrow allograft recipients.

scholarly journals In vivo effect of interleukin-1 alpha on hematopoiesis: role of colony- stimulating factor receptor modulation

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2486-2494
Author(s):  
K Hestdal ◽  
SE Jacobsen ◽  
FW Ruscetti ◽  
CM Dubois ◽  
DL Longo ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Receptor Expression ◽  
Proliferative Potential ◽  
Type I ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Receptor Modulation ◽  
Stimulating Factor

To determine the mechanism(s) by which interleukin-1 (IL-1) promotes granulopoiesis in vivo, we examined the effect of in vivo administration of IL-1 alpha on colony-stimulating factor (CSF) receptor expression on bone marrow cells (BMCs) and whether this directly correlated with progenitor cell responsiveness. Administration of IL-1 alpha to mice induced the upregulation of both granulocyte- macrophage-CSF (GM-CSF) and IL-3 receptors, which reached a maximum 24 hours after IL-1 alpha injection on unfractionated BMCs. This upregulation was more pronounced on the progenitor-enriched cell population (lineage-negative [Lin(-)]). The enhanced GM-CSF and IL-3 receptor expression directly correlated with enhanced IL-3- or GM-CSF- induced growth of colony-forming unit-culture (CFU-c) or CFU-mixture (CFU-Mix; colonies containing macrophages, granulocytes, and erythroid cells). In addition, the absolute number of high proliferative potential-colony-forming cells (HPP-CFC) was increased fivefold. In contrast, granulocyte-CSF (G-CSF)-specific binding on unfractionated BMCs was rapidly (4 hours) reduced after IL-1 alpha administration and returned to control levels by 24 hours. This reduction correlated with IL-1 alpha-induced margination of mature granulocytes (RBC-8C5hi cells), which express high levels of G-CSF receptors. IL-1 alpha treatment did not affect G-CSF receptor expression on Lin- cells. Pretreatment of mice with anti-type I IL-1 receptor antibody blocked the IL-1 alpha-induced upregulation of GM-CSF and IL-3 receptor expression on BMCs. Taken together, as one possible mechanism, IL-1 alpha in vivo may stimulate the expression of functional GM-CSF and IL- 3 receptors on BMCs indirectly, and, in concert with the induction of circulating CSF levels, may account for the ability of IL-1 alpha to stimulate hematopoiesis in vivo.

scholarly journals Post-5-fluorouracil human marrow: stem cell characteristics and renewal properties after autologous marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (9) ◽  
pp. 2283-2289
Author(s):  
FM Stewart ◽  
D Temeles ◽  
P Lowry ◽  
T Thraves ◽  
WW Grosh ◽  
...  
Keyword(s):  
Platelet Count ◽  
Interleukin 1 ◽  
Control Group ◽  
High Dose ◽  
Proliferative Potential ◽  
Colony Stimulating Factor ◽  
Platelet Recovery ◽  
Gm Csf ◽  
Stimulating Factor

The effect of 5-fluorouracil (5-FU) pretreatment on human bone marrow (BM) progenitor/stem cells and recovery of hematopoiesis after autologous marrow transplant was studied. Twenty-one patients were treated with 5-FU (15 mg/kg to 45 mg/kg) intravenously (IV) for 1 to 3 days administered 6 to 22 days before BM harvest. Post-FU marrow was infused into 15 patients after high-dose cyclophosphamide, carmustine (BCNU), and VP-16 (CBV). Seventeen patients (historical controls) were treated with CBV and autologous BM transplantation but did not receive 5-FU before marrow harvest. The groups were comparable for diagnosis and prior therapy. In the 5-FU-treated group and control group, median recovery times for platelet count to 50,000/mm3 were 20 and 30 days, respectively (P = .007), and for platelet count to 100,000/mm3, 23 and 38 days, respectively (P = .007), while neutrophil recovery was not significantly altered. In vitro cultures with 1 to 7 growth factors (interleukin-1 [IL-1], IL-3, IL-4, IL-6, colony-stimulating factor-1 [CSF-1], granulocyte-macrophage colony-stimulating factor [GM-CSF], and G-CSF) were performed. In 8 of 10 patients whose marrow was studied before and after 5-FU treatment, the numbers of CFU-C responsive to the combination of GM-CSF and IL-3 was increased 6.15-fold by 5-FU pretreatment. In 4 of these patients, thymidine suicide of GM-CSF- and IL-3-stimulated CFU-C ranged from 17% to 42%. High proliferative potential colony-forming cell (HPP-CFC) was observed in low frequency in normal marrow and patient's marrow before 5-FU treatment. In 11 of 16 patients pretreated with 5-FU, increased numbers of HPP-CFC were noted. GM-CSF and IL-3 interacted synergistically to stimulate HPP-CFC. Multifactor combinations, especially GM-CSF + G-CSF + IL-3 + IL-6 + IL- 1 + CSF-1 did not increase total colony count or classic HPP-CFC but did result in altered morphology, producing huge, loose colonies. The marrow from patients pretreated with 5-FU is enriched with multifactor- responsive HPP-CFC, renews in vivo granulopoiesis in a manner comparable with marrow harvests without 5-FU pretreatment, and provides accelerated in vivo platelet recovery. This marrow may be an appropriate target marrow for gene insertion in gene-therapy protocols.

scholarly journals In vivo effect of interleukin-1 alpha on hematopoiesis: role of colony- stimulating factor receptor modulation

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2486-2494 ◽  
Author(s):  
K Hestdal ◽  
SE Jacobsen ◽  
FW Ruscetti ◽  
CM Dubois ◽  
DL Longo ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Receptor Expression ◽  
Proliferative Potential ◽  
Type I ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Receptor Modulation ◽  
Stimulating Factor

Abstract To determine the mechanism(s) by which interleukin-1 (IL-1) promotes granulopoiesis in vivo, we examined the effect of in vivo administration of IL-1 alpha on colony-stimulating factor (CSF) receptor expression on bone marrow cells (BMCs) and whether this directly correlated with progenitor cell responsiveness. Administration of IL-1 alpha to mice induced the upregulation of both granulocyte- macrophage-CSF (GM-CSF) and IL-3 receptors, which reached a maximum 24 hours after IL-1 alpha injection on unfractionated BMCs. This upregulation was more pronounced on the progenitor-enriched cell population (lineage-negative [Lin(-)]). The enhanced GM-CSF and IL-3 receptor expression directly correlated with enhanced IL-3- or GM-CSF- induced growth of colony-forming unit-culture (CFU-c) or CFU-mixture (CFU-Mix; colonies containing macrophages, granulocytes, and erythroid cells). In addition, the absolute number of high proliferative potential-colony-forming cells (HPP-CFC) was increased fivefold. In contrast, granulocyte-CSF (G-CSF)-specific binding on unfractionated BMCs was rapidly (4 hours) reduced after IL-1 alpha administration and returned to control levels by 24 hours. This reduction correlated with IL-1 alpha-induced margination of mature granulocytes (RBC-8C5hi cells), which express high levels of G-CSF receptors. IL-1 alpha treatment did not affect G-CSF receptor expression on Lin- cells. Pretreatment of mice with anti-type I IL-1 receptor antibody blocked the IL-1 alpha-induced upregulation of GM-CSF and IL-3 receptor expression on BMCs. Taken together, as one possible mechanism, IL-1 alpha in vivo may stimulate the expression of functional GM-CSF and IL- 3 receptors on BMCs indirectly, and, in concert with the induction of circulating CSF levels, may account for the ability of IL-1 alpha to stimulate hematopoiesis in vivo.

scholarly journals Hematopoietic growth factors released by marrow stromal cells from patients with aplastic anemia

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2256-2261 ◽  
Author(s):  
S Kojima ◽  
T Matsuyama ◽  
Y Kodera
Keyword(s):  
Growth Factors ◽  
Aplastic Anemia ◽  
Stromal Cells ◽  
Culture Media ◽  
Interleukin 1 ◽  
Marrow Stromal Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Stimulating Factor

Abstract We studied the production of granulocyte colony-stimulating factor (G- CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6) by stromal cells from 33 patients with aplastic anemia (AA). Complete, confluent stromal layers were produced by 29 of the 33 samples using the long-term bone marrow culture (LTBMC) system. The concentration of G-CSF, GM-CSF, and IL-6 in culture media with or without interleukin-1 (IL-1) stimulation was determined by an enzyme- linked immunoadsorbent assay (ELISA). The spontaneous production of G- CSF, GM-CSF, and IL-6 did not differ significantly between normal controls and the patients with AA. The ability of stromal cells to release the three hematopoietic growth factors in response to IL-1 was either normal or elevated in all but one patient. We also studied the change in production of G-CSF, GM-CSF, and IL-6 by stromal cells before and after antilymphocyte globulin (ALG) therapy in 16 patients with AA. There was no correlation between the change in production of these cytokines and the response to ALG. In contrast to previous studies that showed a defect in the production of hematopoietic growth factors by stromal cells from patients with AA, the results indicated a normal or elevated production of G-CSF, GM-CSF, and IL-6 by marrow stromal cells in patients with AA.

scholarly journals In vivo modulation with anti-interleukin-1 (IL-1) receptor (p80) antibody 35F5 of the response to IL-1. The relationship of radioprotection, colony-stimulating factor, and IL-6

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 57-62 ◽  
Author(s):  
R Neta ◽  
SN Vogel ◽  
JM Plocinski ◽  
NS Tare ◽  
W Benjamin ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Myeloid Cell ◽  
Natural Resistance ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Relationship Of ◽  
The Relationship ◽  
Stimulating Factor

Abstract Interleukin-1 (IL-1) is radioprotective and induces both circulating colony-stimulating factor(s) (CSF) and IL-6 in mice. We evaluated the relationship among these three responses to IL-1 using anti-IL-1 receptor antibody 35F5. This antibody in vitro blocks responses of T cells and fibroblasts, but not of B cells or myeloid cell lines, to IL- 1. Administration of 35F5 alone before irradiation reduced the number of surviving mice compared with those not treated with 35F5, demonstrating that endogenous IL-1 participates in the natural resistance to radiation. Thirty micrograms of 35F5 per mouse also reduced by 92% the survival of irradiated mice pretreated with 0.3 micrograms of IL-1. Similarly, 30 micrograms of 35F5 reduced by 96% to 98% the induction of IL-6 by IL-1. In contrast, 30 micrograms of 35F5 resulted in only moderate reduction of circulating CSF. Consequently, the level of circulating CSF after 35F5 treatment was still equivalent to levels of CSF that were induced by doses of IL-1 in the radioprotective range. Because treatment with 35F5 antibody resulted in the blocking of IL-1-reduced radioprotection, the above results suggest that circulating CSF, by itself, may not be sufficient for radioprotection. This conclusion supports our previous results which showed that granulocyte-macrophage CSF (GM-CSF) and G-CSF were radioprotective only when administered with suboptimal doses of IL-1.

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