scholarly journals Mechanism of differential inhibition of factor-dependent cell proliferation by transforming growth factor-beta 1: selective uncoupling of FMS from MYC

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2539-2546
Author(s):  
AR Chen ◽  
LR Rohrschneider
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Growth Regulation ◽  
Transforming Growth Factor ◽  
Metabolic Labeling ◽  
Tgf Beta ◽  
Western Blots ◽  
Gm Csf ◽  
Growth Factor Beta

Transforming growth factor-beta 1 (TGF-beta 1) selectively modulates hematopoietic cell proliferation. The proliferation of FDC-P1 clone MAC- 11, a factor-dependent murine myeloid progenitor cell line, was inhibited differentially by TGF-beta 1: strongly in macrophage colony- stimulating factor (M-CSF), mildly in interleukin-3, and not at all in granulocyte-macrophage-CSF (GM-CSF). Flow cytometry and Western blots showed an unexpected increase in expression of FMS, the receptor for M- CSF, in response to TGF-beta 1. Metabolic labeling with 35S-methionine showed that synthesis of FMS protein accelerated in response to TGF- beta 1, whereas its degradation was unaffected. Northern analyses showed a rapid increase in c-fms RNA after the addition of TGF-beta 1. TGF-beta 1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS. However, TGF-beta 1 inhibited the induction by M-CSF of c-myc RNA analyzed on Northern blots and protein detected by radioimmuno-precipitation. TGF-beta 1 did not affect induction of c-myc expression by GM-CSF or induction of c-fos or c-jun by M-CSF. Therefore, FMS and the GM-CSF receptor induce c-myc via signal transduction pathways that differ in that only the former is inhibited by TGF-beta 1. This inhibition may account for the selective growth regulation by TGF-beta 1.

scholarly journals Mechanism of differential inhibition of factor-dependent cell proliferation by transforming growth factor-beta 1: selective uncoupling of FMS from MYC

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2539-2546 ◽  
Author(s):  
AR Chen ◽  
LR Rohrschneider
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Growth Regulation ◽  
Transforming Growth Factor ◽  
Metabolic Labeling ◽  
Tgf Beta ◽  
Western Blots ◽  
Gm Csf ◽  
Growth Factor Beta

Abstract Transforming growth factor-beta 1 (TGF-beta 1) selectively modulates hematopoietic cell proliferation. The proliferation of FDC-P1 clone MAC- 11, a factor-dependent murine myeloid progenitor cell line, was inhibited differentially by TGF-beta 1: strongly in macrophage colony- stimulating factor (M-CSF), mildly in interleukin-3, and not at all in granulocyte-macrophage-CSF (GM-CSF). Flow cytometry and Western blots showed an unexpected increase in expression of FMS, the receptor for M- CSF, in response to TGF-beta 1. Metabolic labeling with 35S-methionine showed that synthesis of FMS protein accelerated in response to TGF- beta 1, whereas its degradation was unaffected. Northern analyses showed a rapid increase in c-fms RNA after the addition of TGF-beta 1. TGF-beta 1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS. However, TGF-beta 1 inhibited the induction by M-CSF of c-myc RNA analyzed on Northern blots and protein detected by radioimmuno-precipitation. TGF-beta 1 did not affect induction of c-myc expression by GM-CSF or induction of c-fos or c-jun by M-CSF. Therefore, FMS and the GM-CSF receptor induce c-myc via signal transduction pathways that differ in that only the former is inhibited by TGF-beta 1. This inhibition may account for the selective growth regulation by TGF-beta 1.

scholarly journals Transforming growth factor beta abrogates the effects of hematopoietins on eosinophils and induces their apoptosis.

1994 ◽  
Vol 179 (3) ◽  
pp. 1041-1045 ◽  
Author(s):  
R Alam ◽  
P Forsythe ◽  
S Stafford ◽  
Y Fukuda
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Gm Csf ◽  
Eosinophil Survival ◽  
Growth Factor Beta ◽  
Induced Apoptosis ◽  
And Function

Hematopoietins, interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) have previously been shown to prolong eosinophil survival and abrogate apoptosis. The objective of this study was to investigate the effect of transforming growth factor beta (TGF-beta) on eosinophil survival and apoptosis. Eosinophils from peripheral blood of mildly eosinophilic donors were isolated to > 97% purity using discontinuous Percoll density gradient. Eosinophils were cultured with hematopoietins with or without TGF-beta for 4 d and their viability was assessed. We confirmed previous observations that hematopoietins prolonged eosinophil survival and inhibited apoptosis. TGF-beta at concentrations > or = 10(-12) M abrogated the survival-prolonging effects of hematopoietins in a dose-dependent manner and induced apoptosis as determined by DNA fragmentation in agarose gels. The effect of TGF-beta was blocked by an anti-TGF-beta antibody. The anti-TGF-beta antibody also prolonged eosinophil survival on its own. The culture of eosinophils with IL-3 and GM-CSF stimulated the synthesis of GM-CSF and IL-5, respectively, suggesting an autocrine mechanism of growth factor production. TGF-beta inhibited the synthesis of GM-CSF and IL-5 by eosinophils. TGF-beta did not have any effect on the expression of GM-CSF receptors on eosinophils. We also studied the effect of TGF-beta on eosinophil function and found that TGF-beta inhibited the release of eosinophil peroxidase. Thus, TGF-beta seems to inhibit eosinophil survival and function. The inhibition of endogenous synthesis of hematopoietins may be one mechanism by which TGF-beta blocks eosinophil survival and induces apoptosis.

scholarly journals Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta.

1986 ◽  
Vol 103 (6) ◽  
pp. 2403-2410 ◽  
Author(s):  
M Laiho ◽  
O Saksela ◽  
P A Andreasen ◽  
J Keski-Oja
Keyword(s):  
Growth Factor ◽  
Plasminogen Activator ◽  
Transforming Growth Factor Beta ◽  
Culture Medium ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Tissue Type ◽  
Metabolic Labeling ◽  
Tgf Beta ◽  
Growth Factor Beta

Cultured human embryonic lung fibroblasts were used as a model to study the effects of transforming growth factor-beta (TGF beta) on the plasminogen activator (PA) activity released by nontumorigenic cells into the culture medium. The cells were exposed to TGF beta under serum-free conditions, and the changes in PA activity and protein metabolism were analyzed by caseinolysis-in-agar assays, zymography, and polypeptide analysis. Treatment of the cells with TGF beta caused a significant decrease in the PA activity of the culture medium as analyzed by the caseinolysis-in-agar assays. The quantitatively most prominent effect of TGF beta on confluent cultures of cells was the induction of an Mr 47,000 protein, as detected by metabolic labeling. The Mr 47,000 protein was a PA inhibitor as judged by reverse zymography. It was antigenically related to a PA inhibitor secreted by HT-1080 tumor cells as demonstrated with monoclonal antibodies. The induced Mr 47,000 inhibitor was deposited into the growth substratum of the cells, as detected by metabolic labeling, immunoblotting analysis, and reverse zymography assays of extracellular matrix preparations. TGF beta also decreased the amounts of urokinase-type and tissue-type PAs accumulated in the conditioned medium, as detected by zymography. Epidermal growth factor antagonized the inhibitory effects of TGF beta by enhancing the amounts of the PAs. These results indicate that growth factors modulate the proteolytic balance of cultured cells by altering the amounts of PAs and their inhibitors.

scholarly journals Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1750-1757 ◽  
Author(s):  
J Lotem ◽  
L Sachs
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Gm Csf ◽  
Cytotoxic Compounds ◽  
Growth Factor Beta ◽  
Induction Of Apoptosis

Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.

scholarly journals Transforming growth factor-beta 1 bifunctionally regulates murine macrophage proliferation

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1679-1685 ◽  
Author(s):  
K Fan ◽  
Q Ruan ◽  
L Sensenbrenner ◽  
B Chen
Keyword(s):  
Growth Factor ◽  
Synergistic Effect ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Promoter ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Gm Csf ◽  
Growth Factor Beta

Abstract Transforming growth factor-beta (TGF-beta) is a family of polypeptide growth factors with multiple functional activities. Recent studies suggest that TGF-beta is a selective inhibitor of hematopoietic cells. In this report, we study the effect of TGF-beta 1 on the proliferation of murine peritoneal exudate macrophages (PEM) in response to purified murine recombinant granulocyte-macrophage colony-stimulating factor (rMuGM-CSF) and human recombinant M-CSF (rHuM-CSF). In mice, PEM and other types of tissue macrophages display multiple types of receptors for CSFs and respond to them, either alone or in combination, to undergo extensive proliferation in vitro. Recombinant human TGF-beta 1 (rHuTGF-beta 1) (0.1 to 1.0 ng/mL) markedly enhanced the growth of PEM in response to rMuGM-CSF but inhibited their responsiveness to rHuM- CSF. Similar effects of rHuTGF-beta 1 were also detected using murine pulmonary alveolar macrophages (PAM) and bone marrow-derived macrophages (BMDM). Receptor binding assays using iodinated rMuGM-CSF and rHuM-CSF showed that rHuTGF-beta 1 treatment greatly enhanced the expression of GM-CSF receptors in PEM, in a time- and dose-dependent manner, suggesting a possible mechanism for the synergistic effect of TGF-beta 1. On the other hand, the expression of M-CSF receptors was not affected by TGF-beta 1 treatment. Analysis by mRNA PCR showed that the synergistic effect of TGF-beta 1 is not due to autocrine CSFs produced by treated cells. Our results suggest that TGF-beta 1 is an important regulator of macrophage proliferation. Depending on the types of CSFs present, TGF-beta 1 may act either as a growth promoter or inhibitor.

scholarly journals Basic fibroblast growth factor counteracts the suppressive effect of transforming growth factor-beta 1 on human myeloid progenitor cells

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 909-915 ◽  
Author(s):  
JL Gabrilove ◽  
G Wong ◽  
E Bollenbacher ◽  
K White ◽  
S Kojima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Fibroblast Growth ◽  
Tgf Beta ◽  
Gm Csf ◽  
Growth Factor Beta

Abstract We have previously shown that basic fibroblast growth factor (bFGF) is mitogenic for human bone marrow stromal cells and enhances myelopoiesis in human long-term bone marrow culture. In the present study, we examined the mechanism by which bFGF enhances granulopoiesis. We observed that bFGF significantly abrogated the inhibitory effect of transforming growth factor-beta 1 (TGF-beta 1) on granulocyte- macrophage colony-stimulating factor (GM-CSF)-supported progenitor cell growth (P = .009). The partial reversal of TGF-beta 1-mediated suppression was dependent on the dose of bFGF used. In addition, we noted that the inclusion of neutralizing antibody to TGF-beta 1 significantly augmented the clonogenic response to GM-CSF. We have also shown that 10 ng/mL or 100 ng/mL of bFGF resulted in a 30% to 100% increase in GM-CSF-mediated progenitor cell growth (P = .0001). These data suggest that bFGF may enhance myelopoiesis by modulating the inhibitory response to TGF-beta 1.

scholarly journals Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

1991 ◽  
Vol 11 (3) ◽  
pp. 1185-1194 ◽  
Author(s):  
P H Howe ◽  
G Draetta ◽  
E B Leof
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Transforming Growth Factor Beta ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
S Phase ◽  
Epithelial Cell Proliferation ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta 1 (TGF beta 1) is a potent inhibitor of epithelial cell proliferation. We present data which indicate that epithelial cell proliferation is inhibited when TGF beta 1 is added throughout the prereplicative G1 phase. Cultures become reversibly blocked in late G1 at the G1/S-phase boundary. The inhibitory effects of TGF beta 1 on cell growth occur in the presence of the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Associated with this inhibitory effect is a decrease in the phosphorylation and histone H1 kinase activity of the p34cdc2 protein kinase. These data suggest that TGF beta 1 growth inhibition in epithelial cells involves the regulation of p34cdc2 activity at the G1/S transition.

scholarly journals Basic fibroblast growth factor counteracts the suppressive effect of transforming growth factor-beta 1 on human myeloid progenitor cells

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 909-915
Author(s):  
JL Gabrilove ◽  
G Wong ◽  
E Bollenbacher ◽  
K White ◽  
S Kojima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Fibroblast Growth ◽  
Tgf Beta ◽  
Gm Csf ◽  
Growth Factor Beta

We have previously shown that basic fibroblast growth factor (bFGF) is mitogenic for human bone marrow stromal cells and enhances myelopoiesis in human long-term bone marrow culture. In the present study, we examined the mechanism by which bFGF enhances granulopoiesis. We observed that bFGF significantly abrogated the inhibitory effect of transforming growth factor-beta 1 (TGF-beta 1) on granulocyte- macrophage colony-stimulating factor (GM-CSF)-supported progenitor cell growth (P = .009). The partial reversal of TGF-beta 1-mediated suppression was dependent on the dose of bFGF used. In addition, we noted that the inclusion of neutralizing antibody to TGF-beta 1 significantly augmented the clonogenic response to GM-CSF. We have also shown that 10 ng/mL or 100 ng/mL of bFGF resulted in a 30% to 100% increase in GM-CSF-mediated progenitor cell growth (P = .0001). These data suggest that bFGF may enhance myelopoiesis by modulating the inhibitory response to TGF-beta 1.

scholarly journals Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1750-1757 ◽  
Author(s):  
J Lotem ◽  
L Sachs
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Gm Csf ◽  
Cytotoxic Compounds ◽  
Growth Factor Beta ◽  
Induction Of Apoptosis

Abstract Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.

scholarly journals Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2379-2385 ◽  
Author(s):  
L Lagneaux ◽  
A Delforge ◽  
C Dorval ◽  
D Bron ◽  
P Stryckmans
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells ◽  
Tgf Beta ◽  
Gm Csf ◽  
Growth Factor Beta

Abstract To explore the pathogenesis of marrow failure in B-cell type chronic lymphocytic leukemia (B-CLL), we have examined the production of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone marrow (BM) derived from B-CLL patients and their capacity to support hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL stromal cells produced G-CSF and GM-CSF in amounts similar to normal stromal layers, whereas IL-6 production was significantly decreased. Using the blast-colony forming cell assay (BI-CFC) and the classical colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that: (1) marrow stromal cells of B-CLL were able to support only 25% of the BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly was partially corrected by the addition of exogenous IL-6; (3) the colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL stromal cells was lower than that of normal CM; (4) that this was the result of the presence of an inhibitor rather that of a growth factor defect; (5) this inhibition could be abrogated by addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6) this antibody corrected the deficient colony supportive activity of the B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was significantly increased in CLL compared with normal; and (8) that this was not caused by the effect of the B- CLL lymphocytes on the stromal cells. It is concluded that this increased TGF-beta production in B-CLL is probably responsible for the decreased IL-6 production by stromal cells and for the inhibiting activity on hematopoietic precursors as well. We hypothesize that TGF- beta generated at a high level by B-CLL marrow stromal cells could play a major role in the pathophysiology of the BM failure seen in advanced stages of B-CLL.

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