scholarly journals Regulation of human monocyte DNA synthesis by colony-stimulating factors, cytokines, and cyclic adenosine monophosphate

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1972-1981 ◽  
Author(s):  
DL Cheung ◽  
JA Hamilton
Keyword(s):  
Dna Synthesis ◽  
Human Peripheral Blood ◽  
Cyclic Adenosine Monophosphate ◽  
Human Monocyte ◽  
Adenosine Monophosphate ◽  
Interleukin 4 ◽  
Murine Macrophage ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulating Factor

Abstract It is reported in this study that a subpopulation of highly purified human peripheral blood human monocytes can proliferate in response to colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony- stimulating factor (GM-CSF), and interleukin-3 (IL-3). Both GM-CSF and IL-3 synergized with CSF-1 for the induction of DNA synthesis. Given the DNA synthesis levels attained, we were able to test the effects of certain cytokines and cyclic adenosine monophosphate (cAMP)-elevating agents, which have been shown to modulate in vitro human myelopoiesis and murine macrophage proliferation. The cytokines, interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF- alpha), as well as cAMP-elevating agents, 8-bromoadenosine 3′:5′-cyclic monophosphate (8BrcAMP), cholera toxin (CT), and prostaglandin E2 (PGE2), suppressed the monocyte DNA synthesis due to CSF-1. These results parallel those reported with human bone marrow progenitors, as well as murine macrophage populations. The cycling human monocyte population could provide a model cell type to understand the molecular events controlling human myelopoiesis.

scholarly journals Regulation of human monocyte DNA synthesis by colony-stimulating factors, cytokines, and cyclic adenosine monophosphate

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1972-1981
Author(s):  
DL Cheung ◽  
JA Hamilton
Keyword(s):  
Dna Synthesis ◽  
Human Peripheral Blood ◽  
Cyclic Adenosine Monophosphate ◽  
Human Monocyte ◽  
Adenosine Monophosphate ◽  
Interleukin 4 ◽  
Murine Macrophage ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulating Factor

It is reported in this study that a subpopulation of highly purified human peripheral blood human monocytes can proliferate in response to colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony- stimulating factor (GM-CSF), and interleukin-3 (IL-3). Both GM-CSF and IL-3 synergized with CSF-1 for the induction of DNA synthesis. Given the DNA synthesis levels attained, we were able to test the effects of certain cytokines and cyclic adenosine monophosphate (cAMP)-elevating agents, which have been shown to modulate in vitro human myelopoiesis and murine macrophage proliferation. The cytokines, interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF- alpha), as well as cAMP-elevating agents, 8-bromoadenosine 3′:5′-cyclic monophosphate (8BrcAMP), cholera toxin (CT), and prostaglandin E2 (PGE2), suppressed the monocyte DNA synthesis due to CSF-1. These results parallel those reported with human bone marrow progenitors, as well as murine macrophage populations. The cycling human monocyte population could provide a model cell type to understand the molecular events controlling human myelopoiesis.

Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1206-1214 ◽  
Author(s):  
RL Rosen ◽  
KD Winestock ◽  
G Chen ◽  
X Liu ◽  
L Hennighausen ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Peripheral Blood ◽  
Janus Kinase ◽  
Lower Molecular Weight ◽  
Colony Stimulating Factor ◽  
Enhancer Element ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway. Recent studies have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5. To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage- CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms. Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule. Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element. Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A. STAT5A-STAT5A homodimers and STAT5A- STAT5B heterodimers formed in response to GM-CSF. Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR. Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF.

scholarly journals Differentiation of human dendritic cells from monocytes in vitro using granulocyte-macrophage colony stimulating factor and low concentration of interleukin-4

2003 ◽  
Vol 60 (5) ◽  
pp. 531-538 ◽  
Author(s):  
Miodrag Colic ◽  
Dusan Jandric ◽  
Zorica Stojic-Vukanic ◽  
Jelena Antic-Stankovic ◽  
Petar Popovic ◽  
...  
Keyword(s):  
T Cells ◽  
Interleukin 4 ◽  
Adherent Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Alloreactive T Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Dendritic Cells ◽  
Stimulating Factor

Several laboratories have developed culture systems that allow the generation of large numbers of human dendritic cells (DC) from monocytes using granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-4 (IL-4). In this work we provided evidence that GM-CSF (100 ng/ml) in combination with a low concentration of IL-4 (5 ng/ml) was efficient in the generation of immature, non-adherent, monocyte-derived DC as the same concentration of GM-CSF, and ten times higher concentration of IL-4 (50 ng/ml). This conclusion was based on the similar phenotype profile of DC such as the expression of CD1a, CD80, CD86, and HLA-DR, down-regulation of CD14, and the absence of CD83, as well as on their similar allostimulatory activity for T cells. A higher number of cells remained adherent in cultures with lower concentrations of IL-4 than in cultures with higher concentrations of the cytokine. However, most of these adherent cells down-regulated CD14 and stimulated the proliferation of alloreactive T cells. In contrast adherent cells cultivated with GM-CSF alone were predominantly macrophages as judged by the expression of CD14 and the inefficiency to stimulate alloreactive T cells. DC generated in the presence of lower concentrations of IL-4 had higher proapoptotic potential for the Jurkat cell line than DC differentiated with higher concentrations of IL-4, suggesting their stronger cytotoxic, anti-tumor effect.

scholarly journals Interleukin-4 gene expression in activated human T lymphocytes is regulated by the cyclic adenosine monophosphate-dependent signaling pathway

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 691-698 ◽  
Author(s):  
P Borger ◽  
HF Kauffman ◽  
DS Postma ◽  
E Vellenga
Keyword(s):  
T Lymphocytes ◽  
Signaling Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Interleukin 4 ◽  
Con A ◽  
Activated T Cells ◽  
Gm Csf ◽  
Dose Dependent ◽  
Dependent Signaling Pathway

In the present study, we have investigated the involvement of the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway on interleukin-4 (IL-4) gene expression in freshly isolated human T lymphocytes. 2′–0-dibutyryl cAMP (db-cAMP) and prostaglandin E2 (PGE2) were used to directly and indirectly activate the protein kinase A pathway. Northern analysis showed that concanavalin A (Con A)-, anti- CD3 (alpha CD3)-, or anti-CD3 plus anti-CD28 (alpha CD3/alpha CD28)- induced accumulation of IL-4 mRNA was inhibited by db-cAMP (10(-3) mol/L). Db-cAMP showed a steep dose-dependent inhibition; concentrations or = 10(-4) mol/L did not affect IL-4 mRNA accumulation. In contrast, GM-CSF mRNA expression showed a wider dose- dependent range; 10(-5) mol/L db-cAMP still affected GM-CSF accumulation. PGE2 inhibited the Con A- and alpha CD3/alpha CD28- induced accumulation of IL-4 mRNA in a dose-dependent fashion. Con A- induced IL-4 mRNA was inhibited by 10(-4) to 10(-7) mol/L PGE2; alpha CD3/alpha CD28-induced IL-4 mRNA was inhibited by 10(-5) to 10(-8) mol/L PGE2. Nuclear run-on experiments showed that the inhibitory effects of db-cAMP and PGE2 were accomplished at transcriptional level in Con A-activated T cells, whereas changes at transcriptional and posttranscriptional level were involved in alpha CD3/alpha CD28- activated T lymphocytes. In contrast to Con A and alpha CD3/alpha CD28 activation, phorbol myristate acetate plus A23187-induced IL-4 mRNA expression was insensitive to the inhibitory effect of db-cAMP and PGE2. Moreover, it appeared that the sensitivity for cAMP-mediated downregulation could not be blocked by stimulation T lymphocytes with alpha CD3/alpha CD28 in the presence of IL-2, IL-7, IL-10, IL-12, or a combination of these cytokines. Finally, it was shown that, in accordance with the mRNA studies, db-cAMP and PGE2 suppressed the IL-4 secretion in Con A- and alpha CD3/alpha CD28-activated T cells. In conclusion, these data show that IL-4 expression is negatively regulated by the protein kinase A-dependent signaling pathway by transcriptional and posttranscriptional mechanisms that depend on costimulatory signals.

scholarly journals Recombinant human granulocyte/macrophage colony-stimulating factor activates intracellular killing of Leishmania donovani by human monocyte-derived macrophages.

1987 ◽  
Vol 166 (5) ◽  
pp. 1436-1446 ◽  
Author(s):  
W Y Weiser ◽  
A Van Niel ◽  
S C Clark ◽  
J R David ◽  
H G Remold
Keyword(s):  
Leishmania Donovani ◽  
Human Monocyte ◽  
Peripheral Blood Monocyte ◽  
Antileishmanial Activity ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) obtained from cloned complementary Mo cell DNA and expressed in COS-1 cells activates cultured peripheral blood monocyte-derived macrophages in vitro to become cytotoxic for intracellular L. donovani. The antileishmanial effect of rGM-CSF, which can be completely neutralized by anti-rGM-CSF antiserum, is maximal after 36 h preincubation with the cultured macrophages, compared with that of rIFN-gamma, which reaches its maximum at 72 h of preincubation. The antileishmanial effect of GM-CSF as well as IFN-gamma is independent of detectable amounts of LPS and is not augmented by the addition of 10 or 50 ng/ml of LPS. Simultaneous administration of suboptimal doses of rGM-CSF and rIFN-gamma to monocyte-derived macrophages results in greater antileishmanial activity by these cells than administration of either lymphokine alone, although no enhancement of antileishmanial activity is observed when optimal doses of these two lymphokines are applied together.

scholarly journals The Meningococcal Adhesin NhhA Provokes Proinflammatory Responses in Macrophages via Toll-Like Receptor 4-Dependent and -Independent Pathways

2012 ◽  
Vol 80 (11) ◽  
pp. 4027-4033 ◽  
Author(s):  
Mikael Sjölinder ◽  
Georg Altenbacher ◽  
Xiao Wang ◽  
Yumin Gao ◽  
Charlotta Hansson ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Gene Activation ◽  
Adaptor Protein ◽  
Human Monocyte ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Proinflammatory Responses ◽  
Macrophage Colony ◽  
Related Proteins ◽  
Stimulating Factor

ABSTRACTActivation of macrophages by Toll-like receptors (TLRs) and functionally related proteins is essential for host defense and innate immunity. TLRs recognize a wide variety of pathogen-associated molecules. Here, we demonstrate that the meningococcal outer membrane protein NhhA has immunostimulatory functions and triggers release of proinflammatory cytokines from macrophages. NhhA-induced cytokine release was found to proceed via two distinct pathways in RAW 264.7 macrophages. Interleukin-6 (IL-6) secretion was dependent on activation of TLR4 and required the TLR signaling adaptor protein MyD88. In contrast, release of tumor necrosis factor (TNF) was TLR4 and MyD88 independent. Both pathways involved NF-κB-dependent gene regulation. Using a PCR-based screen, we could identify additional targets of NhhA-dependent gene activation such as the cytokines and growth factors IL-1α, IL-1β, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In human monocyte-derived macrophages, G-CSF, GM-CSF, and IL-6 were found to be major targets of NhhA-dependent gene regulation. NhhA induced transcription of IL-6 and G-CSF mRNA via TLR4-dependent pathways, whereas GM-CSF transcription was induced via TLR4-independent pathways. These data provide new insights into the role of NhhA in host-pathogen interaction.

scholarly journals Macrophage colony-stimulating factor and granulocyte-macrophage colony- stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3616-3621 ◽  
Author(s):  
JA Hamilton ◽  
GA Whitty ◽  
H Stanton ◽  
J Wojta ◽  
M Gallichio ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Human Monocyte ◽  
Mrna Levels ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Pai 1

Macrophage colony-stimulating factor (M-CSF or CSF-1) and granulocyte- macrophage CSF (GM-CSF) have been shown to increase human monocyte urokinase-type plasminogen-activator (u-PA) activity with possible consequences for cell migration and tissue remodeling; because monocyte u-PA activity is likely to be controlled in part also by the PA inhibitors (PAIs) made by the cell, the effect of M-CSF and GM-CSF on human monocyte PAI-2 and PAI-1 synthesis was investigated. To this end, elutriation-purified human monocytes were treated in vitro with purified recombinant human M-CSF and GM-CSF, and PAI-2 and PAI-1 antigen and mRNA levels measured by specific enzyme-linked immunosorbent assays and Northern blot, respectively. Each CSF could enhance the protein and mRNA levels of PAI-2 and PAI-1 at similar concentrations for each product. This similar regulation of monocyte PAI expression in response to the CSFs contrasted with that found for the effects of lipopolysaccharide, transforming growth factor-beta and a glucocorticoid. Therefore, PAIs may be modulating the effects of the CSFs on monocyte u-PA activity at sites of inflammation and tissue remodeling.

scholarly journals Production of granulocyte-macrophage colony-stimulating factor by large granular lymphocytes stimulated with Candida albicans: role in activation of human neutrophil function

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2259-2265 ◽  
Author(s):  
DK Blanchard ◽  
MB Michelini-Norris ◽  
JY Djeu
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Yeast Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Granular Lymphocytes

In the present study, culture supernatants from larger granular lymphocytes (LGL) that were activated with Candida albicans antigens were shown to stimulate the ability of neutrophils to inhibit fungal growth. Identification of the activation factors showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor, was involved. Human peripheral blood mononuclear cells were fractionated by Percoll density centrifugation and each subpopulation of cells was stimulated with C albicans yeast cells. GM-CSF was produced in those fractions enriched for LGL, but not T lymphocytes or adherent monocytes. Additionally, the phenotype of the GM-CSF-producing cell was found to be CD2+, CD16+, HLA-DR+, and negative for CD4, CD8, and CD15. Kinetic studies demonstrated that GM- CSF appeared in the supernatants within 2 days of culture and continued to be produced up to 7 days. Optimal stimulation of LGL was seen at a ratio of 3 heat-killed C albicans yeast cells per LGL. Thus, LGL play an important role in host defense against this opportunistic pathogen by producing cytokines, including GM-CSF, which in turn activates the fungicidal activity of neutrophils.

scholarly journals Actions of human interleukin-4/B-cell stimulatory factor-1 on proliferation and differentiation of enriched hematopoietic progenitor cells in culture

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1615-1621 ◽  
Author(s):  
Y Sonoda ◽  
T Okuda ◽  
S Yokota ◽  
T Maekawa ◽  
Y Shizumi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Early Stage ◽  
Direct Action ◽  
Interleukin 4 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Progenitor Cell Proliferation ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract We studied the effects of recombinant human interleukin-4 (IL-4) on colony formation by enriched hematopoietic progenitors. IL-4 alone did not support colony formation at all. When IL-4 was combined with granulocyte colony-stimulating factor (G-CSF), the number of pure neutrophil colonies increased three times over that supported by G-CSF alone. IL-4 added 5 days after the addition of G-CSF failed to exert this synergistic effect, indicating that IL-4 acts on the early stage of proliferation. The mapping experiments (sequential observation of colony formation) have clearly shown that IL-4 did not initiate progenitor cell proliferation. Based on these data, IL-4 may possess a direct action on progenitor cells; however, it can only act as a costimulant with G-CSF. In contrast, IL-4 had possible inhibitory effects on macrophage colony formation supported by interleukin-3 (IL- 3) and macrophage colony-stimulating factor (M-CSF). In other words, IL- 4 may induce progenitor cells to become sensitive to G-CSF and thereby induce neutrophil differentiation. Delayed addition experiments demonstrated that human IL-4, unlike murine IL-4, could support neither proliferation nor survival of erythroid burst or mixed colony forming cells. Neutrophil colony forming cells only survived and recovered after addition of G-CSF and erythropoietin on day 5 of incubation. On the other hand, IL-3 supported neutrophil, erythroid burst, and mixed colony forming cells as reported previously (Sonoda et al, Proc Natl Acad Sci USA, 85:4360, 1988). These results led us to propose that IL-4 possibly acts with more mature progenitor cells than those of IL-3 or granulocyte-macrophage (GM)-CSF.

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