Interactions between TGF-beta and adrenocorticotropin in growth regulation of human adrenal fetal zone cells

1994 ◽  
Vol 266 (3) ◽  
pp. E495-E500
Author(s):  
A. K. Stankovic ◽  
W. E. Grizzle ◽  
C. R. Stockard ◽  
C. R. Parker
Keyword(s):  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Growth Regulation ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Intrauterine Development ◽  
Sigma Chemical ◽  
And Function

The factors that regulate growth and function of the human adrenal gland during intrauterine development and thereafter are ill defined. Whereas others have reported that adrenocorticotropic hormone (ACTH) augments the inhibitory effect of transforming growth factor-beta (TGF-beta) on growth of fetal zone (FZ) cells of the human fetal adrenal, we recently found that ACTH interferes with TGF-beta's inhibition of growth of fetal adrenal neocortex cells. In this study we sought to assess independently the effects of TGF-beta in the absence and presence of ACTH on growth of FZ cells. TGF-beta, in a time- and dose-dependent manner, inhibited growth (i.e., [3H]thymidine incorporation) of FZ cells. ACTH (Cortrosyn), at 90 pM to 90 nM, was found to interfere with the TGF-beta inhibition of FZ growth. ACTH 1-24 and human ACTH 1-39, both from Sigma Chemical, also were found to blunt the response of FZ cells to TGF-beta. Growth inhibition due to TGF-beta action and the reversal by ACTH of TGF-beta effects on FZ cell growth were confirmed by the results of immunohistochemical analyses of 5'-bromo-2'-deoxyuridine incorporation into nuclei of FZ cells and by indirect evaluations of cell numbers. Both forskolin (10 microM) and dibutyryl adenosine 3',5'-cyclic monophosphate (1 mM), but not phorbol 12-myristate 13-acetate (1 or 100 mM), were able to mimic ACTH actions in blunting the inhibitory effects of TGF-beta on DNA synthesis. We conclude that ACTH, possibly via activation of adenylate cyclase, interferes with, rather than augments, the growth-inhibitory effect of TGF-beta on FZ cell growth.

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 Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1737-1741 ◽  
Author(s):  
T Ishibashi ◽  
SL Miller ◽  
SA Burstein
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Ache Activity ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Significant Inhibition ◽  
Tgf Beta ◽  
Megakaryocytic Differentiation

Abstract To investigate the potential role of platelets in the inhibition of megakaryocytopoiesis, freeze-thawed extracts of human platelets were added to serumless liquid cultures of murine marrow. When acetylcholinesterase (AchE), a marker of megakaryocytic differentiation in mice, was assayed, a significant inhibition of enzymatic activity was noted in cultures containing the equivalent of greater than 5 X 10(6) solubilized platelets per milliliter. Freeze-thawed extracts of granulocytes had significantly less inhibitory effect than did platelets. Transforming growth factor beta (TGF-beta), a growth factor known to be inhibitory to some cell lineages and to be found at relatively high concentrations in platelets, was then added to liquid marrow cultures. A similar inhibition of AchE activity was detected when cultures were stimulated with mitogen-stimulated conditioned medium. The effect was potent with 50% inhibition of AchE activity observed at 4 pmol TGF-beta/L. To determine if TGF-beta inhibited specifically one aspect of megakaryocytic differentiation, the factor was added to isolated single megakaryocytes in serumless culture induced by interleukin 3 (IL3) to increase in size. The number of megakaryocytes increasing in size in response to IL 3 exposure was reduced from 68% to 20% when both factors were simultaneously added to cultures. Colony assays showed that megakaryocytic and granulocyte- macrophage colony detection was inhibited at picomolar concentrations of the factor. These data suggest that TGF-beta is a potent in vitro inhibitor of the murine megakaryocytic lineage, although its effects are not limited to this lineage.

Expression and secretion of transforming growth factor-beta by bleomycin-stimulated rat alveolar macrophages

1993 ◽  
Vol 264 (1) ◽  
pp. L36-L42 ◽  
Author(s):  
E. M. Denholm ◽  
S. M. Rollins
Keyword(s):  
Growth Factor ◽  
Alveolar Macrophages ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Chemotactic Activity ◽  
Beta Activity ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Growth Factor Beta

Bleomycin-induced fibrosis in rodents has been used extensively as a model of human pulmonary fibrosis. The influx of monocytes observed during the early stages of fibrosis is at least partially regulated by the elaboration of chemotactic factors in the lung. Exposure of alveolar macrophages (AM phi) to bleomycin either in vivo or in vitro stimulated secretion of monocyte chemotactic activity (MCA). This MCA has been previously characterized as being primarily due to fibronectin fragments. The present experiments revealed that bleomycin also induced AM phi to secrete a second chemotactic factor, transforming growth factor-beta (TGF-beta). However, the TGF-beta secreted by macrophages was in latent form, since no TGF-beta activity was detected unless AM phi conditioned medium (CM) was acid-activated. After acidification, chemotactic activity in CM from AM phi stimulated with bleomycin in vitro was increased by 3.6, whereas activity in AM phi CM from fibrotic rats increased by 2 and that of a bleomycin-stimulated AM phi cell line increased by 1.6. This acid-activatable chemotactic activity was inhibited by antibody to TGF-beta. Bleomycin-stimulated AM phi s secreted significantly more TGF-beta than did unstimulated controls. Further, in vitro exposure of AM phi to bleomycin induced TGF-beta mRNA expression in a time- and concentration-dependent manner, with maximal mRNA being detected following a 16-h incubation with 1 microgram/ml bleomycin.

scholarly journals Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides.

1991 ◽  
Vol 174 (4) ◽  
pp. 925-929 ◽  
Author(s):  
J Hatzfeld ◽  
M L Li ◽  
E L Brown ◽  
H Sookdeo ◽  
J P Levesque ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Colony Formation ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Tgf Beta ◽  
Hematopoietic Progenitors ◽  
Single Cell Culture ◽  
Growth Factor Beta ◽  
Blocking Antibodies

We have used antisense oligonucleotides to study the roles of transforming growth factor beta (TGF-beta) and the two antioncogenes, retinoblastoma susceptibility (Rb) and p53, in the negative regulation of proliferation of early hematopoietic cells in culture. The antisense TGF-beta sequence significantly enhanced the frequency of colony formation by multi-lineage, early erythroid, and granulomonocytic progenitors, but did not affect colony formation by late progenitors. Single cell culture and limiting dilution analysis indicated that autocrine TGF-beta is produced by a subpopulation of early progenitors. Antisense Rb but not antisense p53 yielded similar results in releasing multipotential progenitors (colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) from quiescence. Rb antisense could partially reverse the inhibitory effect of exogenous TGF-beta. Anti-TGF-beta blocking antibodies, antisense TGF-beta, or Rb oligonucleotides all had similar effects. No additive effects were observed when these reagents were combined, suggesting a common pathway of action. Our results are consistent with the model that autocrine production of TGF-beta negatively regulates the cycling status of early hematopoietic progenitors through interaction with the Rb gene product.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals

1992 ◽  
Vol 12 (1) ◽  
pp. 302-308
Author(s):  
M T Diaz-Meco ◽  
I Dominguez ◽  
L Sanz ◽  
M M Municio ◽  
E Berra ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Phospholipase C ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Transduction Mechanisms ◽  
Growth Factor Beta ◽  
Mitogenic Signal Transduction ◽  
Hydrolysis Of

Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1.

scholarly journals Ability of flt3 ligand to stimulate the in vitro growth of primitive murine hematopoietic progenitors is potently and directly inhibited by transforming growth factor-beta and tumor necrosis factor-alpha

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5016-5026 ◽  
Author(s):  
SE Jacobsen ◽  
OP Veiby ◽  
J Myklebust ◽  
C Okkenhaug ◽  
SD Lyman
Keyword(s):  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Growth Factor Beta ◽  
Necrosis Factor

The recently cloned flt3 ligand (FL) stimulates the growth of primitive hematopoietic progenitor cells through synergistic interactions with multiple other cytokines. The present study is the first demonstrating cytokines capable of inhibiting FL-stimulated hematopoietic cell growth. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta l) potently inhibited the clonal growth of murine Lin-Sca-l+ bone marrow progenitors stimulated by FL alone or in combination with granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), interleukin (IL)-3, IL-6, IL-11, or IL-12. TGF-beta 1 inhibited more than 96% of the myeloid colony formation in response to these cytokine combinations, whereas TNF-alpha reduced the number of colonies by 58% to 96% depending on the cytokine by which FL was combined. In addition, both TNF-alpha and TGF-beta 1 inhibited more than 90% of B220+ cell production from B220- bone marrow cells stimulated by FL + IL-7. The effects of TNF-alpha and TGF-beta 1 appeared to be due to a direct effect and on the early progenitors because the inhibition was observed at the single cell level, and because delayed addition of the two inhibitors for only 48 hours dramatically reduced their inhibitory effects. A neutralizing anti-TGF- beta antibody showed the presence of endogenous TGF-beta in the cultures and potently enhanced the ability of FL to stimulate progenitor cell growth in the absence of other cytokines. Agonistic antibodies specifically activating the p75 TNF receptors were more efficient than wild type murine TNF-alpha in signaling growth inhibition of Lin-Sca-l+ progenitor cells, whereas the p55 agonist had less effect than murine TNF-alpha. Finally, TGF-beta increased the number of FL + IL-11-stimulated Lin-Sca-1+ cells in the G1 phase of the cell cycle with 76%, whereas TNF-alpha only had a marginal effect on cell cycle distribution. Thus, TGF-beta, TNF-alpha, and p75 TNF receptor agonists are potent direct inhibitors of FL-stimulated progenitor cell growth in vitro.

scholarly journals Transforming growth factor beta directly regulates primitive murine hematopoietic cell proliferation

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 596-602 ◽  
Author(s):  
JR Keller ◽  
IK Mcniece ◽  
KT Sill ◽  
LR Ellingsworth ◽  
PJ Quesenberry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bone Marrow Cells ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Hematopoietic Progenitor ◽  
Growth Factor Beta ◽  
Dose Dependent

Abstract We previously reported that transforming growth factor beta (TGF-beta) selectively inhibits colony-stimulating factor-driven hematopoietic progenitor cell growth. We report here that TGF-beta 1 can act directly on hematopoietic progenitors to inhibit the growth of the most primitive progenitors measurable in vitro. Highly enriched populations of hematopoietic progenitor cells were obtained by isolating lineage negative (Lin-), Thy-1-positive (Thy-1+) fresh bone marrow cells, or by isolating cells from interleukin-3 (IL-3) supplemented bone marrow cultures expressing Thy-1 antigen with the fluorescent activated cell sorter. TGF-beta 1 inhibited IL-3-induced Thy-1 expression on Thy-1- negative (Thy-1-) bone marrow cells in a dose-dependent manner with an ED50 of 5 to 10 pmol/L. In addition, TGF-beta 1 inhibited the formation of multipotent and mixed colonies by isolated Thy-1+ cells, while single lineage granulocyte and macrophage colonies were not affected. The growth of Thy-1+ Lin- cells incubated as single cells in Terasaki plates in medium supplemented with IL-3 were inhibited by TGF-beta, demonstrating a direct inhibitory effect. Hematopoietic stem cells, which have a high proliferative potential (HPP) when responding to combinations of growth factors in vitro, have been detected in the bone marrow of normal mice and mice surviving a single injection of 5- fluorouracil. TGF-beta 1 inhibited the growth of all subpopulations of HPP colony forming cells (CFC) in a dose-dependent manner with an ED50 of 5 to 10 pmol/L. Thus, TGF-beta directly inhibits the growth of the most immature hematopoietic cells measurable in vitro.

scholarly journals Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells.

1993 ◽  
Vol 120 (4) ◽  
pp. 995-1002 ◽  
Author(s):  
R Flaumenhaft ◽  
M Abe ◽  
Y Sato ◽  
K Miyazono ◽  
J Harpel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Muscle Cells ◽  
Beta Activity ◽  
Dependent Manner ◽  
Tgf Beta

Transforming growth factor beta (TGF-beta) is released from cells in a latent form consisting of the mature growth factor associated with an aminoterminal propeptide and latent TGF-beta binding protein (LTBP). The endogenous activation of latent TGF-beta has been described in co-cultures of endothelial and smooth muscle cells. However, the mechanism of this activation remains unknown. Antibodies to native platelet LTBP and to a peptide fragment of LTBP inhibit in a dose-dependent manner the activation of latent TGF-beta normally observed when endothelial cells are cocultured with smooth muscle cells. Inhibition of latent TGF-beta activation was also observed when cells were co-cultured in the presence of an excess of free LTBP. These data represent the first demonstration of a function for the LTBP in the extracellular regulation of TGF-beta activity and indicate that LTBP participates in the activation of latent TGF-beta, perhaps by concentrating the latent growth factor on the cell surface where activation occurs.

scholarly journals A growth factor for cardiac myocytes is produced by cardiac nonmyocytes.

1991 ◽  
Vol 2 (12) ◽  
pp. 1081-1095 ◽  
Author(s):  
C S Long ◽  
C J Henrich ◽  
P C Simpson
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cardiac Myocytes ◽  
Transforming Growth Factor Beta ◽  
Cardiac Myocyte ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Hypertrophic Growth

Cardiac nonmyocytes, primarily fibroblasts, surround cardiac myocytes in vivo. We examined whether nonmyocytes could modulate myocyte growth by production of one or more growth factors. Cardiac myocyte hypertrophic growth was stimulated in cultures with increasing numbers of cardiac nonmyocytes. This effect of nonmyocytes on myocyte size was reproduced by serum-free medium conditioned by the cardiac nonmyocytes. The majority of the nonmyocyte-derived myocyte growth-promoting activity bound to heparin-Sepharose and was eluted with 0.75 M NaCl. Several known polypeptide growth factors found recently in cardiac tissue, namely acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF alpha), and transforming growth factor beta 1 (TGF beta 1), also caused hypertrophy of cardiac myocytes in a dose-dependent manner. However, the nonmyocyte-derived growth factor (tentatively named NMDGF) could be distinguished from these other growth factors by different heparin-Sepharose binding profiles (TNF alpha, aFGF, bFGF, and TGF beta 1) by neutralizing growth factor-specific antisera (PDGF, TNF alpha, aFGF, bFGF, and TGF beta 1), by the failure of NMDGF to stimulate phosphatidylinositol hydrolysis (PDGF and TGF beta 1), and, finally, by the apparent molecular weight of NMDGF (45-50 kDa). This nonmyocyte-derived heparin-binding growth factor may represent a novel paracrine growth mechanism in myocardium.

scholarly journals BMP-4 inhibits follicle-stimulating hormone secretion in ewe pituitary

2005 ◽  
Vol 186 (1) ◽  
pp. 109-121 ◽  
Author(s):  
M-O Faure ◽  
L Nicol ◽  
S Fabre ◽  
J Fontaine ◽  
N Mohoric ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Hormone Secretion ◽  
Inhibitory Effect ◽  
Type I ◽  
Mrna Levels ◽  
Dependent Manner

Activins and inhibins, members of the transforming growth factor-beta family are able to stimulate and inhibit, respectively, FSH synthesis and release. Other members of this superfamily, the bone morphogenetic proteins (BMPs), may also affect FSH synthesis in the mouse. The aim of this work was to determine whether BMPs are expressed in the ovine pituitary and whether they play a role in the regulation of FSH release. The mRNAs encoding BMP-2, BMP-4, BMP-7 and the oocyte-derived growth factor, growth differentiation factor (GDF)-9 were detected in the pituitaries of cyclic ewes by reverse-transcriptase PCR, as well as the mRNAs encoding the BMP type I receptors, BMPR-IA (activin-receptor-like kinase (ALK)-3) and BMPR-IB (ALK-6), and type II receptors (BMPR-II). Immunolabeling of pituitary sections revealed the presence of BMPR-IA (ALK-3) and BMPR-II in gonadotrope cells. To investigate the potential effects of BMPs on FSH secretion, ewe pituitary cell cultures were treated with BMP-4 (10−11 M to 10−9 M) for 48 h. Interestingly, FSH release was decreased in a dose-dependent manner. At 10−9 M BMP-4 both FSH concentration and FSHβ mRNA expression were reduced by 40% of control values. In contrast, there was no inhibitory effect on either LH or LHβ mRNA expression. A similar result was found with BMP-6. BMP-4 triggered the phosphorylation of Smad1, suggesting that the effect of BMP-4 on FSH secretion is due to the activation of the BMPs signaling pathway. Furthermore, BMP-4 blocked the stimulatory effect of activin on both FSH release and FSHβ mRNA and amplified the suppression of FSH release and FSHβ mRNA levels induced by 17β-estradiol. These results indicate that a functional BMP system operates within the sheep pituitary, at least in vitro, to decrease FSH release and to modulate the effect of activin.

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