Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4102-4108 ◽  
Author(s):  
Holger Bartz ◽  
Nicole M. Avalos ◽  
Andrea Baetz ◽  
Klaus Heeg ◽  
Alexander H. Dalpke
Keyword(s):  
Bone Marrow Cells ◽  
Functional Differentiation ◽  
Precursor Cells ◽  
Cytokine Signaling ◽  
Inhibitory Effects ◽  
Gm Csf ◽  
Dendritic Cell Differentiation ◽  
Maturation Stages ◽  
Macrophage Colony

Abstract Dendritic cells (DCs) are important sentinels within innate immunity, monitoring the presence of infectious microorganisms. They operate in 2 different maturation stages, with transition from immature to mature DCs being induced by activation of toll-like receptors (TLRs). However, TLRs are also expressed on precursor cells of DCs. Here we analyzed the effects of TLR stimulation during the process of granulocyte-macrophage–colony-stimulating factor (GM-CSF)–mediated in vitro generation of immature DCs from precursor cells. We show that TLR triggering deviated phenotypic and functional differentiation from CD14+ monocytes to CD1a+ DCs. Similar results were obtained when differentiation of murine myeloid DCs from bone marrow cells was analyzed. The inhibitory effects were independent of soluble factors. TLR stimulation in DC precursor cells induced proteins of the suppressor of cytokine signaling family (SOCS), which correlated with loss of sensitivity to GM-CSF. Overexpression of SOCS-1 abolished GM-CSF signal transduction. Moreover, forced SOCS-1 expression in DC precursors mimicked the inhibitory effects on DC generation observed for TLR stimulation. The results indicate that TLR stimulation during the period of DC generation interferes with and deviates DC differentiation and that these effects are mediated particularly by SOCS-1.

scholarly journals Role of cytokines in sustaining long-term human megakaryocytopoiesis in vitro

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 332-337 ◽  
Author(s):  
RA Briddell ◽  
JE Brandt ◽  
TB Leemhuis ◽  
R Hoffman
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Gm Csf ◽  
Liquid Suspension ◽  
Bone Marrow Cultures ◽  
Macrophage Colony

An in vitro liquid suspension culture system was used to determine the role of cytokines in sustaining long-term human megakaryocytopoiesis. Bone marrow cells expressing CD34 but not HLA-DR (CD34+DR-) were used as the inoculum of cells to initiate long-term bone marrow cultures (LTBMC). CD34+DR- cells (5 x 10(3)/mL) initially contained 0.0 +/- 0.0 assayable colony-forming unit-megakaryocytes (CFU-MK), 6.2 +/- 0.4 assayable burst-forming unit-megakaryocytes (BFU-MK), and 0.0 +/- 0.0 megakaryocytes (MK). LTBMCs were recharged every 48 hours with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 1 alpha (IL-1 alpha), IL-3, and/or IL-6, alone or in combination. LTBMCs were demidepopulated weekly or biweekly, the number of cells and MK enumerated, and then assayed for CFU-MK and BFU-MK. LTBMCs receiving no cytokine(s) contained no assayable CFU-MK or BFU-MK and no observable MK. LTBMCs receiving GM-CSF, IL-1 alpha, and/or IL-3 contained assayable CFU-MK and MK but no BFU-MK for 10 weeks of culture. The effects of GM-CSF and IL-3, IL-1 alpha and IL-3, but not GM-CSF and IL-1 alpha were additive with regards to their ability to augment the numbers of assayable CFU-MK during LTBMC. LTBMCs supplemented with IL-6 contained modest numbers of assayable CFU-MK for only 4 weeks; this effect was not additive to that of GM-CSF, IL-1 alpha, or IL-3. The addition of GM-CSF, IL-1 alpha, and IL-3 alone or in combination each led to the appearance of significant numbers of MKs during LTBMC. By contrast, IL-6 supplemented cultures contained relatively few MK. These studies suggest that CD34+DR- cells are capable of initiating long-term megakaryocytopoiesis in vitro and that a hierarchy of cytokines exists capable of sustaining this process.

Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells [see comments]

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2599-2605 ◽  
Author(s):  
XG Zhang ◽  
R Bataille ◽  
M Jourdan ◽  
S Saeland ◽  
J Banchereau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL- 6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.

scholarly journals Role of cytokines in sustaining long-term human megakaryocytopoiesis in vitro

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 332-337 ◽  
Author(s):  
RA Briddell ◽  
JE Brandt ◽  
TB Leemhuis ◽  
R Hoffman
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Gm Csf ◽  
Liquid Suspension ◽  
Bone Marrow Cultures ◽  
Macrophage Colony

Abstract An in vitro liquid suspension culture system was used to determine the role of cytokines in sustaining long-term human megakaryocytopoiesis. Bone marrow cells expressing CD34 but not HLA-DR (CD34+DR-) were used as the inoculum of cells to initiate long-term bone marrow cultures (LTBMC). CD34+DR- cells (5 x 10(3)/mL) initially contained 0.0 +/- 0.0 assayable colony-forming unit-megakaryocytes (CFU-MK), 6.2 +/- 0.4 assayable burst-forming unit-megakaryocytes (BFU-MK), and 0.0 +/- 0.0 megakaryocytes (MK). LTBMCs were recharged every 48 hours with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 1 alpha (IL-1 alpha), IL-3, and/or IL-6, alone or in combination. LTBMCs were demidepopulated weekly or biweekly, the number of cells and MK enumerated, and then assayed for CFU-MK and BFU-MK. LTBMCs receiving no cytokine(s) contained no assayable CFU-MK or BFU-MK and no observable MK. LTBMCs receiving GM-CSF, IL-1 alpha, and/or IL-3 contained assayable CFU-MK and MK but no BFU-MK for 10 weeks of culture. The effects of GM-CSF and IL-3, IL-1 alpha and IL-3, but not GM-CSF and IL-1 alpha were additive with regards to their ability to augment the numbers of assayable CFU-MK during LTBMC. LTBMCs supplemented with IL-6 contained modest numbers of assayable CFU-MK for only 4 weeks; this effect was not additive to that of GM-CSF, IL-1 alpha, or IL-3. The addition of GM-CSF, IL-1 alpha, and IL-3 alone or in combination each led to the appearance of significant numbers of MKs during LTBMC. By contrast, IL-6 supplemented cultures contained relatively few MK. These studies suggest that CD34+DR- cells are capable of initiating long-term megakaryocytopoiesis in vitro and that a hierarchy of cytokines exists capable of sustaining this process.

Mad2 (Mitotic Arrest Deficiency 2) Is Essential for the Synergistic Proliferation Induced by Stem Cell Factor Combined with GM-CSF in Hematopoietic Progenitor Cells, Effects Reflecting the Association of c-kit with Mad2.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 71-71
Author(s):  
Shigeki Ito ◽  
Charlie Mantel ◽  
Myung-Kwan Han ◽  
Seiji Fukuda ◽  
Yoji Ishida ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Cytokine Signaling ◽  
Mouse Bone Marrow ◽  
Wild Type ◽  
Gm Csf ◽  
Kinetics Of ◽  
Marrow Cells

Abstract Mitotic spindle checkpoint protein, Mad2, is required for proper functioning of the mitotic checkpoint which ensures correct chromosome segregation during cell division. Homozygous Mad2 gene deletion is embryonic-lethal. Mad2 interacts with mitosis-associated molecules such as Mad1 and anaphase promoting complex/cyclosome to ensure proper cell cycle progression. Recently, Mad2 was shown to physically associate with the common beta chain of the GM-CSF receptor which raises the possibility that Mad2 may also be involved in cytokine signaling and regulation of mitosis in hematopoietic progenitor cells. To investigate this, we studied hematopoiesis and cytokine signaling in Mad2-haploinsufficient (+/−) mutant mice (M2MT). Colony formation by granulocyte macrophage progenitor cells (CFU-GM) from bone marrow of wild type (WT) mice is synergistically stimulated in vitro by the combination of stem cell factor (SCF) and GM-CSF. We found that bone marrow CFU-GM from M2MT mice are deficient in the synergistic proliferative/colony formation response in vitro to stimulation with the combination of GM-CSF plus SCF. In contrast, there was no difference in stimulation of CFU-GM formation in response to the individual cytokines, GM-CSF or SCF alone, nor a difference in response to pokeweed mitogen mouse spleen cell conditioned medium between M2MT and WT mice. Because there was no difference in the frequency of c-kit+Sca-1+Lin- (KSL) cells nor a difference in the intensity of c-kit surface expression on KSL cells from wild type and M2MT mice, we considered whether the suppression of the SCF/GM-CSF synergy response was due to a difference in intracellular growth-factor receptor signaling pathways. We found that the kinetics of Erk1/2 phosphorylation signaling differ in M2MT Lin- cells compared to WT Lin- cells and that the duration of Erk1/2 phosphorylation in M2MT cells was at least one half of that in WT Lin- cells. On the other hand, we found no difference in the kinetics of Akt phosphorylation between WT and M2MT Lin- cells suggesting a specificity of involvement of the MAP-kinase pathways. To understand how Mad2 plays a role in SCF/GM-CSF synergy, we tested the physical interaction between Mad2 and c-kit in primary Lin- mouse bone marrow cells. Primary Lin- bone marrow cells from WT mice were expanded in liquid culture with SCF and thrombopoietin for 5 days. We found that Mad2 physically associated with c-kit as indicated by co-immunoprecipitation. These results suggest that Mad2 is required for the SCF/GM-CSF proliferative-synergy response in primary Lin- mouse bone marrow cells and that Mad2 is involved in growth-factor signaling pathways, such as the MAP-kinase cascade, in addition to spindle checkpoint function in primary hematopoietic cells. These effects are likely mediated through Mad2 interaction with c-kit and the beta chain of the GM-CSF receptor.

scholarly journals Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells [see comments]

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2599-2605 ◽  
Author(s):  
XG Zhang ◽  
R Bataille ◽  
M Jourdan ◽  
S Saeland ◽  
J Banchereau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL- 6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.

Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 639-645 ◽  
Author(s):  
Peter D. Emanuel ◽  
Richard C. Snyder ◽  
Tonya Wiley ◽  
Balaganesh Gopurala ◽  
Robert P. Castleberry
Keyword(s):  
Signal Transduction ◽  
Colony Growth ◽  
Juvenile Myelomonocytic Leukemia ◽  
Farnesyltransferase Inhibitors ◽  
Inhibitory Effects ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Dose Dependent

Juvenile myelomonocytic leukemia (JMML) is an early childhood disease for which there is no effective therapy. Therapy with 13-cis retinoic acid or low-dose chemotherapy can induce some responses, but neither mode is curative. Stem cell transplantation can produce lasting remissions but is hampered by high rates of relapse. The pathogenesis of JMML involves deregulated cytokine signal transduction through the Ras signaling pathway, with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor (GM-CSF). A JMML mouse model, achieved through homozygous deletion of the neurofibromatosis gene, confirmed the involvement of deregulated Ras in JMML pathogenesis. With this pathogenetic knowledge, mechanism-based treatments are now being developed and tested. Ras is critically dependent on a prenylation reaction for its signal transduction abilities. Farnesyltransferase inhibitors are compounds that were developed specifically to block the prenylation of Ras. Two of these compounds, L-739,749 and L-744,832, were tested for their ability to inhibit spontaneous JMML granulocyte-macrophage colony growth. Within a dose range of 1 to 10 μmol/L, each compound demonstrated dose-dependent inhibition of JMML colony growth. An age-matched patient with a different disease and GM-CSF–stimulated normal adult marrow cells also demonstrated dose-dependent inhibitory effects on colony growth, but they were far less sensitive to these compounds than JMML hematopoietic progenitors. Even if the addition of L-739,749 were delayed for 5 days, significant inhibitory effects would still show in JMML cultures. These results demonstrate that a putative Ras-blocking compound can have significant growth inhibitory effects in vitro, perhaps indicating a potential treatment for JMML.

IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF– and GM-CSF–deficient mice

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 3978-3985 ◽  
Author(s):  
Francesca Walker ◽  
Hui-Hua Zhang ◽  
Vance Matthews ◽  
Janet Weinstock ◽  
Edouard C. Nice ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Alternative Pathway ◽  
Conditioned Media ◽  
Colony Stimulating Factor ◽  
Double Knockout ◽  
Gm Csf ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor

AbstractMice defective in both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have severely impaired neutrophil production and function, yet these mice respond to acute pathogen challenge with a significant neutrophil response. We have recently reported the development of an in vitro system to detect granulopoietic cytokines secreted from cells isolated from G-CSF, GM-CSF double knockout mice. The conditioned media produced by these cells after stimulation with lipopolysaccharide or Candida albicans supports the production and differentiation of granulocytes (ie, the conditioned media contains neutrophil promoting activity [NPA]). We now show that the NPA in the G-CSF−/−/GM-CSF−/− conditioned media requires interleukin-6 (IL6), is abolished by soluble gp130, and can be specifically immunodepleted by an anti-IL6R antibody. NPA effects on bone marrow cells are also mimicked by Hyper-IL6, and the soluble IL6R is present in NPA. These results show that the IL6/sIL6R complex is the major effector of NPA. NPA production by mice defective for both G-CSF and GM-CSF uncovers an alternative pathway to granulocyte production, which is activated after exposure to pathogens.

scholarly journals Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 238-246 ◽  
Author(s):  
Esther Carreras ◽  
Sean Turner ◽  
Mark Barton Frank ◽  
Nicholas Knowlton ◽  
Jeanette Osban ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factor ◽  
Estrogen Receptor Alpha ◽  
Bone Marrow Cells ◽  
Early Stage ◽  
Gm Csf ◽  
Dendritic Cell Differentiation ◽  
Estrogen Receptor Signaling ◽  
Macrophage Colony

Abstract During inflammation, elevated granulocyte macrophage–colony-stimulating factor (GM-CSF) directs the development of new dendritic cells (DCs). This pathway is influenced by environmental factors, and we previously showed that physiologic levels of estradiol, acting through estrogen receptor alpha (ERα), promote the GM-CSF–mediated differentiation of a CD11b+ DC subset from myeloid progenitors (MPs). We now have identified interferon regulatory factor 4 (IRF4), a transcription factor induced by GM-CSF and critical for CD11b+ DC development in vivo, as a target of ERα signaling during this process. In MPs, ERα potentiates and sustains GM-CSF induction of IRF4. Furthermore, retroviral delivery of the Irf4 cDNA to undifferentiated ERα−/− bone marrow cells restored the development of the estradiol/ERα-dependent DC population, indicating that an elevated amount of IRF4 protein substitutes for ERα signaling. Thus at an early stage in the MP response to GM-CSF, ERα signaling induces an elevated amount of IRF4, which leads to a developmental program underlying CD11b+ DC differentiation.

scholarly journals Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4105-4114 ◽  
Author(s):  
W Piacibello ◽  
L Fubini ◽  
F Sanavio ◽  
MF Brizzi ◽  
A Severino ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Leukemia Cell ◽  
Precursor Cells ◽  
In Vitro Growth ◽  
Hematopoietic Growth Factors ◽  
Phosphorylated Protein ◽  
Gm Csf

A novel hematopoietic growth factor for primitive hematopoietic progenitor cells, the ligand for the flt3/flk2 receptor, (FL), has been recently purified and its gene has been cloned. In the present study, we investigated the effects of FL on the proliferation and differentiation of normal and leukemic myeloid progenitor cells. We demonstrate that FL is a potent stimulator of the in vitro growth of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin- 3 (IL-3), or G-CSF-dependent granulocyte-macrophage committed precursors from Lin- CD34+ bone marrow cells of normal donors. By contrast, FL does not affect the growth of erythroid-committed progenitors even in the presence of erythropoietin. The effect of FL on the proliferation and on the in vitro growth of clonogenic leukemic precursor cells was studied in 54 acute myeloid leukemia (AML) cases. Fresh leukemia blasts from 36 of 45 patients with AML significantly responded to FL without any relation to the French-American-British (FAB) subtype. FL stimulated the proliferation of leukemic blasts in a dose-dependent fashion. Synergistic activities were seen when FL was combined with G-CSF, GM-CSF, IL-3, or stem cell factor (SCF). FL as a single factor induced or increased significantly colony formation by clonogenic precursor cells from 21 of 24 patients with AML. In the presence of suboptimal and optimal concentrations of G-CSF, GM-CSF, IL3, SCF, or a combination of all factors, FL strongly enhanced the number of leukemic colonies (up to 18-fold). We also evaluated the induction of tyrosine phosphorylated protein on FL stimulation in fresh AML cells. We demonstrate that, on FL stimulation, a band of phosphorylated protein(s) of about 90 kD can be detected in FL- responsive, but not in FL-unresponsive cases. This study suggests that FL may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor with other cytokines.

scholarly journals Construction of Recombinant Human GM-CSF and GM-CSF-ApoA-I Fusion Protein and Evaluation of Their Biological Activity

2021 ◽  
Vol 14 (5) ◽  
pp. 459
Author(s):  
Mariya Pykhtina ◽  
Svetlana Miroshnichenko ◽  
Vladimir Romanov ◽  
Antonina Grazhdantseva ◽  
Galina Kochneva ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
E Coli ◽  
Gm Csf ◽  
Human Apolipoprotein ◽  
Proliferative Effect ◽  
Erythroleukemia Cells ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

In this study, two strains of the yeast P. pastoris were constructed, one of which produced authentic recombinant human granulocyte-macrophage colony-stimulating factor (ryGM-CSF), and the other was a chimera consisting of ryGM-CSF genetically fused with mature human apolipoprotein A-I (ApoA-I) (ryGM-CSF-ApoA-I). Both forms of the cytokine were secreted into the culture medium. The proteins’ yield during cultivation in flasks was 100 and 60 mg/L for ryGM-CSF and ryGM-CSF-ApoA-I, respectively. Both forms of recombinant GM-CSF stimulated the proliferation of human TF-1 erythroleukemia cells; however, the amount of chimera required was 10-fold that of authentic GM-CSF to induce a similar proliferative effect. RyGM-CSF exhibited a 2-fold proliferative effect on BFU-E (burst-forming units—erythroid) at a concentration 1.7 fold less than non-glycosylated E. coli-derived GM-CSF. The chimera together with authentic ryGM-CSF increased the number of both erythroid precursors and BMC granulocytes after 48 h of incubation of human bone marrow cells (BMCs). In addition, the chimeric form of ryGM-CSF was more effective at increasing the viability of the total amount of BMCs, decreasing apoptosis compared to the authentic form. ryGM-CSF-ApoA-I normalized the proliferation, maturation, and segmentation of neutrophils within the physiological norm, preserving the pool of blast cells under conditions of impaired granulopoiesis. The chimera form of GM-CSF exhibited the properties of a multilinear growth factor, modulating the activity of GM-CSF and, perhaps, it may be more suitable for the normalization of granulopoiesis.

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