scholarly journals Mechanisms of tumor necrosis factor-granulocyte-macrophage colony- stimulating factor-induced dendritic cell development

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3019-3028 ◽  
Author(s):  
F Santiago-Schwarz ◽  
N Divaris ◽  
C Kay ◽  
SE Carsons
Keyword(s):  
Dendritic Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cell Development ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract In a previous report, we described that tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically enhanced the development of dendritic cell (DC) progeny from early stem cells and that there is a common monocyte-DC progenitor cell. Low levels of DC were obtained with GM-CSF alone, and TNF by itself failed to induce stem cell development. Here, we investigate mechanisms by which TNF and GM-CSF institute increases in DC, and how these same molecules support later stages of DC differentiation. We show that TNF is required as the first signal, that there is upregulation of GM-CSF receptors (GM-CSFRs), and that TNF inhibits the differentiation of colony-forming units-granulocyte. High levels of GM- CSFR were always associated with conditions yielding a large number of DC, and a kinetic analysis showed a close ontogenic relationship between DC and GM-CSFR levels. The addition of anti-GM-CSF or anti-TNF antibodies blocked synergistic responses related to DC development, including high levels of GM-CSFRs. Anti-GM-CSF was the most potent inhibitor of proliferation (80%) and macrophage, DC, and polymorphonuclear (PMN) cell development. With polyclonal anti-TNF, inhibition was less (35%), and there was a shift from myelomonocytic and DC to PMN progeny. Our results support the concept that receptor upregulation is an important mechanism for growth factor synergy. Our data also indicate that the opposing effects of TNF on hematopoiesis contribute to the selection of the DC pathway and emphasize the importance of GM-CSFRs not only in initiated DC development, but also in controlling DC viability and function.

scholarly journals Mechanisms of tumor necrosis factor-granulocyte-macrophage colony- stimulating factor-induced dendritic cell development

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3019-3028 ◽  
Author(s):  
F Santiago-Schwarz ◽  
N Divaris ◽  
C Kay ◽  
SE Carsons
Keyword(s):  
Dendritic Cell ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cell Development ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

In a previous report, we described that tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically enhanced the development of dendritic cell (DC) progeny from early stem cells and that there is a common monocyte-DC progenitor cell. Low levels of DC were obtained with GM-CSF alone, and TNF by itself failed to induce stem cell development. Here, we investigate mechanisms by which TNF and GM-CSF institute increases in DC, and how these same molecules support later stages of DC differentiation. We show that TNF is required as the first signal, that there is upregulation of GM-CSF receptors (GM-CSFRs), and that TNF inhibits the differentiation of colony-forming units-granulocyte. High levels of GM- CSFR were always associated with conditions yielding a large number of DC, and a kinetic analysis showed a close ontogenic relationship between DC and GM-CSFR levels. The addition of anti-GM-CSF or anti-TNF antibodies blocked synergistic responses related to DC development, including high levels of GM-CSFRs. Anti-GM-CSF was the most potent inhibitor of proliferation (80%) and macrophage, DC, and polymorphonuclear (PMN) cell development. With polyclonal anti-TNF, inhibition was less (35%), and there was a shift from myelomonocytic and DC to PMN progeny. Our results support the concept that receptor upregulation is an important mechanism for growth factor synergy. Our data also indicate that the opposing effects of TNF on hematopoiesis contribute to the selection of the DC pathway and emphasize the importance of GM-CSFRs not only in initiated DC development, but also in controlling DC viability and function.

scholarly journals Administration of recombinant human granulocyte-macrophage colony- stimulating factor after chemotherapy regulates the expression and secretion of monocyte tumor necrosis factor (TNF) and TNF receptors p55 and p75

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4234-4242 ◽  
Author(s):  
MA Williams ◽  
I Kouroumoussis ◽  
D Syndercombe-Court ◽  
L Hendry ◽  
AC Newland ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Biologically Active ◽  
Colony Stimulating Factor ◽  
Tnf Receptors ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Monocyte expression and secretion of tumor necrosis factor (TNF) and TNF receptors (TNF-R) p55 and p75 was studied in patients receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) after intensive chemotherapy. TNF expression and secretion of biologically active TNF was increased at regeneration compared with that of patients who had received chemotherapy alone. This effect persisted for several weeks after cessation of growth factor therapy. GM-CSF restored the responsiveness of monocytes to bacterial lipopolysaccharide (LPS), which appeared to be diminished after chemotherapy alone. Expression and secretion of TNF-R p55 and p75 by monocytes was augmented by GM-CSF therapy in association with the increase in TNF protein. We propose that GM-CSF administration after chemotherapy restores the normal responsiveness of monocytes to a secondary stimulus such as LPS and primes monocytes to respond to LPS with increased expression and secretion of TNF and TNF-R.

scholarly journals Recombinant tumor necrosis factor enhances the proliferative responsiveness of murine peripheral macrophages to macrophage colony- stimulating factor but inhibits their proliferative responsiveness to granulocyte-macrophage colony-stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1627-1632
Author(s):  
BD Chen ◽  
M Mueller
Keyword(s):  
Tumor Necrosis Factor ◽  
Proliferative Response ◽  
Tumor Necrosis ◽  
Colony Stimulating Factor ◽  
Short Term Treatment ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is a protein produced by activated macrophages in response to endotoxin. The effect of recombinant murine TNF (rMuTNF) on the growth of murine tissue-derived macrophage colony- forming units (CFU-M) which are responsive to both macrophage and granulocyte-macrophage colony-stimulating factors (M-CSF and GM-CSF), was studied. TNF alone did not stimulate macrophage proliferation but did prolong their survival in vitro. The proliferative response of CFU- M to M-CSF, however, was greatly enhanced by the presence of TNF. The enhancement effect of TNF is dose-dependent, reaching a maximum at approximately 50 U/mL. In contrast, the proliferative responsiveness of CFU-M to GM-CSF was inhibited by the concurrent addition of rMuTNF. Both effects appear to be caused directly by rMuTNF, rather than by the secondary factor(s) produced by TNF-treated macrophages. TNF treatment also induced a transient downmodulation of M-CSF receptors in cultured macrophages and accelerated their uptake and use of exogenous M-CSF, which may account for, at least in part, the enhanced proliferative activity in response to M-CSF. Short-term treatment (24 hours) was not sufficient to induce either an enhancing or an inhibitory effect upon CFU-M. This study suggests an autoregulatory role for TNF in the production of mature tissue macrophages by selectively enhancing their proliferative response to lineage specific growth factor, M-CSF.

scholarly journals Production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte- macrophage colony-stimulating factor [see comments]

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1368-1374 ◽  
Author(s):  
SD Sisson ◽  
CA Dinarello
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract Recent studies have examined the synergistic effects of granulocyte- macrophage colony-stimulating factor (GM-CSF) and hematopoietin-1 (now identified as Interleukin-1, IL-1) on bone marrow colony formation. In the present report, human peripheral blood mononuclear cells (MNCs) were stimulated in vitro with recombinant human GM-CSF (rGM-CSF) and production of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF) was measured by specific radioimmunoassays. In the MNCs of 20 individuals, rGM-CSF's ability to induce the three cytokines was variable. Nearly all donors responded to low-dose rGM-CSF (0.02 to 2 ng/mL) with production of TNF, whereas some individuals did not produce IL-1 alpha or IL-1 beta. The MNCs from some subjects stimulated with high-dose rGM-CSF (10 to 80 ng/mL) produced as much cytokine as in response to 10 ng/mL endotoxin. Localization (ie, extracellular or cell- associated cytokine) was specific for the cytokine rather than the stimulus. Indomethacin increased the amount of cytokine produced in response to rGM-CSF for IL-1 beta and TNF but not for IL-1 alpha. In addition, interferon-gamma (INF-gamma) upregulated the amount of TNF induced by rGM-CSF in all donors examined, with variable effect on IL-1 alpha and IL-1 beta. Suboptimal levels of endotoxin incubated with rGM- CSF did not alter the amount of IL-1 produced as compared with cells stimulated with rGM-CSF alone, whereas TNF production showed either no change or a slight decrease in production. These data suggest that GM- CSF may play an important role in the host defense response by stimulating production of these cytokines.

Modulation of Granulocyte-Macrophage Colony-Stimulating Factor Gene Expression by a Tumor Necrosis Factor  Specific Ribozyme in Juvenile Myelomonocytic Leukemic Cells

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4263-4268
Author(s):  
Per Ole Iversen ◽  
Mouldy Sioud
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Tnf Gene ◽  
Stimulating Factor ◽  
Necrosis Factor

The human cytokines tumor necrosis factor  (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both promote growth and survival of malignant cells from children with juvenile myelomonocytic leukemia (JMML). It has been postulated that TNF stimulates GM-CSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF gene expression by a catalytic RNA molecule (ribozyme) also downregulated the expression of GM-CSF in JMML cells. GM-CSF protein, GM-CSF–dependent colony formation, and viability of JMML cells were reduced. The observed effect was specific, because synthesis of interleukin-1β, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory effect of TNF on GM-CSF gene expression in JMML cells probably takes place at the transcription level, because the ribozyme treatment decreased GM-CSF mRNA. No apparent toxicity of the ribozyme was detected in normal bone marrow progenitor cells. Thus, the inhibition of TNF gene expression in JMML cells by ribozymes may be a novel therapeutic approach for this disorder.

Modulation of Granulocyte-Macrophage Colony-Stimulating Factor Gene Expression by a Tumor Necrosis Factor  Specific Ribozyme in Juvenile Myelomonocytic Leukemic Cells

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4263-4268 ◽  
Author(s):  
Per Ole Iversen ◽  
Mouldy Sioud
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Tnf Gene ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract The human cytokines tumor necrosis factor  (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both promote growth and survival of malignant cells from children with juvenile myelomonocytic leukemia (JMML). It has been postulated that TNF stimulates GM-CSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF gene expression by a catalytic RNA molecule (ribozyme) also downregulated the expression of GM-CSF in JMML cells. GM-CSF protein, GM-CSF–dependent colony formation, and viability of JMML cells were reduced. The observed effect was specific, because synthesis of interleukin-1β, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory effect of TNF on GM-CSF gene expression in JMML cells probably takes place at the transcription level, because the ribozyme treatment decreased GM-CSF mRNA. No apparent toxicity of the ribozyme was detected in normal bone marrow progenitor cells. Thus, the inhibition of TNF gene expression in JMML cells by ribozymes may be a novel therapeutic approach for this disorder.

scholarly journals Production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte- macrophage colony-stimulating factor [see comments]

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1368-1374 ◽  
Author(s):  
SD Sisson ◽  
CA Dinarello
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Recent studies have examined the synergistic effects of granulocyte- macrophage colony-stimulating factor (GM-CSF) and hematopoietin-1 (now identified as Interleukin-1, IL-1) on bone marrow colony formation. In the present report, human peripheral blood mononuclear cells (MNCs) were stimulated in vitro with recombinant human GM-CSF (rGM-CSF) and production of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF) was measured by specific radioimmunoassays. In the MNCs of 20 individuals, rGM-CSF's ability to induce the three cytokines was variable. Nearly all donors responded to low-dose rGM-CSF (0.02 to 2 ng/mL) with production of TNF, whereas some individuals did not produce IL-1 alpha or IL-1 beta. The MNCs from some subjects stimulated with high-dose rGM-CSF (10 to 80 ng/mL) produced as much cytokine as in response to 10 ng/mL endotoxin. Localization (ie, extracellular or cell- associated cytokine) was specific for the cytokine rather than the stimulus. Indomethacin increased the amount of cytokine produced in response to rGM-CSF for IL-1 beta and TNF but not for IL-1 alpha. In addition, interferon-gamma (INF-gamma) upregulated the amount of TNF induced by rGM-CSF in all donors examined, with variable effect on IL-1 alpha and IL-1 beta. Suboptimal levels of endotoxin incubated with rGM- CSF did not alter the amount of IL-1 produced as compared with cells stimulated with rGM-CSF alone, whereas TNF production showed either no change or a slight decrease in production. These data suggest that GM- CSF may play an important role in the host defense response by stimulating production of these cytokines.

scholarly journals Recombinant tumor necrosis factor enhances the proliferative responsiveness of murine peripheral macrophages to macrophage colony- stimulating factor but inhibits their proliferative responsiveness to granulocyte-macrophage colony-stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1627-1632 ◽  
Author(s):  
BD Chen ◽  
M Mueller
Keyword(s):  
Tumor Necrosis Factor ◽  
Proliferative Response ◽  
Tumor Necrosis ◽  
Colony Stimulating Factor ◽  
Short Term Treatment ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract Tumor necrosis factor (TNF) is a protein produced by activated macrophages in response to endotoxin. The effect of recombinant murine TNF (rMuTNF) on the growth of murine tissue-derived macrophage colony- forming units (CFU-M) which are responsive to both macrophage and granulocyte-macrophage colony-stimulating factors (M-CSF and GM-CSF), was studied. TNF alone did not stimulate macrophage proliferation but did prolong their survival in vitro. The proliferative response of CFU- M to M-CSF, however, was greatly enhanced by the presence of TNF. The enhancement effect of TNF is dose-dependent, reaching a maximum at approximately 50 U/mL. In contrast, the proliferative responsiveness of CFU-M to GM-CSF was inhibited by the concurrent addition of rMuTNF. Both effects appear to be caused directly by rMuTNF, rather than by the secondary factor(s) produced by TNF-treated macrophages. TNF treatment also induced a transient downmodulation of M-CSF receptors in cultured macrophages and accelerated their uptake and use of exogenous M-CSF, which may account for, at least in part, the enhanced proliferative activity in response to M-CSF. Short-term treatment (24 hours) was not sufficient to induce either an enhancing or an inhibitory effect upon CFU-M. This study suggests an autoregulatory role for TNF in the production of mature tissue macrophages by selectively enhancing their proliferative response to lineage specific growth factor, M-CSF.

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