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PubMed2005

Transforming growth factor-beta3 induces pleurodesis in rabbits and collagen production of human mesothelial cells.

STUDY OBJECTIVE: The aim of this study was to examined whether transforming growth factor (TGF)-beta(3) induces pleurodesis in rabbits and collagen production by human pleural mesothelial cells in vitro. DESIGN: A combined animal and in vitro study. METHODS: TGF-beta(3) was injected intrapleurally in rabbits at the following doses: 0.167 mug, 0.5 mug, 1.67 mug, and 5 mug (five rabbits per group). The rabbits were killed 14 days following injection, and pleurodesis was graded from 1 (none) to 8 (complete symphysis). Pleural mesothelial cell cultures were established from benign pleural effusions and treated with TGF-beta(3) for 48 h at the following doses: 0 (control), 5 ng/mL, 1.5 ng/mL, 5 ng/mL, and 15 ng/mL and 50 ng/mL (two independent experiments). Collagen I messenger RNA (mRNA) expression was quantified using real-time polymerase chain reaction. RESULTS: The median pleurodesis score was 5 (interquartile range [IQR], 4.5) in the 0.167-mug group, 6 (IQR, 5) in the 0.5-mug group, 8 (IQR, 1) in the 1.67-mug group, and 8 (IQR, 0.5) in the 5-mug group (p = 0.012). Higher TGF-beta(3) doses induced the production of significantly more pleural fluid than the lower doses (p = 0.005). The pleural fluid induced by higher doses contained significantly lower numbers of nucleated cells (p = 0.014) and lactate dehydrogenase levels (p = 0.013) than the pleural fluid induced by lower doses of the agent. TGF-beta(3) markedly enhanced collagen I mRNA expression by the human pleural mesothelial cells. This effect peaked at 5 ng/mL TGF-beta(3). With this dose of TGF-beta(3), the collagen I mRNA expression was increased 16-fold over control levels. CONCLUSION: TGF-beta(3) causes a dose-dependent pleurodesis when administered intrapleurally in rabbits, and induces collagen messenger RNA synthesis from human pleural mesothelial cells.

Animals↗
PubMed2001

Overexpression of transforming growth factor-beta3 immunohistochemical staining in extramammary Paget's disease, but downregulated expression in Bowen's disease.

BACKGROUND: The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex, with some reports indicating a tumor inhibition role and others indicating a tumor promotion role. In particular, TGF-beta3 is thought to play a key role in controlling epithelial homeostasis. Immunopositive p53 has been demonstrated in a variety of human malignant tumors and its role in oncogenesis and tumor progression is thought to be important. Extramammary Paget's disease (EPD) and Bowen's disease are skin cancers of unknown histogenesis. OBJECTIVE: To clarify the role of TGF-beta3 and p53 in EPD and Bowen's disease and to better understand the origin of these disorders. METHODS: Specimens were obtained from 12 patients with EPD and 12 patients with Bowen's disease seen at our clinic between 1993 and 2000. TGF-beta3 and p53 immunohistochemical staining was performed. RESULTS: In three of the 12 EPD patients and five of the 12 Bowen's disease patients, positive p53 staining was detected. In contrast, TGF-beta3 overexpression was detected in all EPD patients, whereas downregulated TGF-beta3 expression was detected in all Bowen's disease patients. CONCLUSIONS: The present data suggest different roles for TGF-beta3 in abnormal epidermal cells in EPD and Bowen's disease. Thus, TGF-beta3 expression may be modulated differently via a p53-dependent or -independent pathway in the pathogenesis of EPD and Bowen's disease. Moreover, high TGF-beta expression appears to be a useful indicator of tumor activity in EPD.

Aged↗
PubMed2003

Cross-talk between interleukin-6 and transforming growth factor-beta3 regulates extracellular matrix production by human fibroblasts from subjects with non-syndromic cleft lip and palate.

BACKGROUND: Transforming growth factor-beta (TGF-beta) interference with interleukin 6 (IL-6) activity and the role of the latter in early human embryonic development prompted us to examine the effects IL-6 on matrix synthesis and the effects of TGF-beta3 on IL-6 expression human cleft lip and palate (CLP) fibroblasts. METHODS: Collagen and glycosaminoglycan (GAG) synthesis were determined by radiolabeled precursors and biglycan expression by Northern blotting before and after adding IL-6. The effects of TGF-beta3 on IL-6 production were assayed by evaluating IL-6 transcript by Northern blotting and IL-6 protein secretion by enzyme-linked immunosorbent assay. RESULTS: The results showed that IL-6 elicited an inhibitory effect on collagen and GAG levels in CLP fibroblasts by lowering hyaluronan and dermatan sulfate secretion. IL-6 up-regulated biglycan expression, but less strongly than TGF-beta3. TGF-beta3 significantly down-regulated IL-6 transcript and secretion in CLP fibroblasts. CONCLUSIONS: These data suggest the increase in matrix components that characterize the CLP fibroblast phenotype might be due to a concerted TGF-beta3-IL-6 action. We hypothesize changes in cross-talk between TGF-beta3 and IL-6 signal transduction pathways are involved in the induction of cleft palate.

Analysis of Variance↗
PubMedDate not supplied

Patterns of epidermal growth factor receptor, basic fibroblast growth factor and transforming growth factor-beta3 expression in skin with chronic venous insufficiency.

Growth factors which act as signalling peptides through specific cell surface receptors are involved in functions such as cell proliferation, migration, and differentiation. Here, we report on alterations of the epidermal growth factor receptor (EGFR), basic fibroblast growth factor (bFGF) and transforming growth factor beta3 (TGF-beta3) expression patterns in the skin at various stages of chronic venous insufficiency (CVI). Thirty punch biopsies were taken from patients with CVI and growth factors or the growth factor receptor were detected by indirect immunofluorescence and immunoperoxidase techniques. EGFR, bFGF, and TGF-beta3 expression is strongly increased in the stroma of venous eczema and in leg ulcer skin, and to a lesser extent in the dermis of patients with lipodermatosclerosis. Venous eczema and lipodermatosclerosis epidermis show an elevated EGFR and bFGF synthesis throughout all strata. In the different CVI stages, telangiectases and reticular veins and pigmentation EGFR and bFGF staining are limited to the basal layer. We conclude that the alterations in the expression of EGFR, bFGF and TGF-beta3 precede changes in the affected skin within progressing stages of CVI. The exact mechanisms of growth factor involvement in the pathogenesis of venous ulceration remain to be resolved.

Aged↗
PubMed2006

Differential interactions between transforming growth factor-beta3/TbetaR1, TAB1, and CD2AP disrupt blood-testis barrier and Sertoli-germ cell adhesion.

The biochemical basis that regulates the timely and selective opening of the blood-testis barrier (BTB) to migrating preleptotene/leptotene spermatocytes at stage VIII of the epithelial cycle in adult rat testes is virtually unknown. Recent studies have shown that cytokines (e.g. transforming growth factor (TGF)-beta3) may play a crucial role in this event. However, much of this information relies on the use of toxicants (e.g. CdCl(2)), making it difficult to relay these findings to normal testicular physiology. Here we report that overexpression of TGF-beta3 in primary Sertoli cells cultured in vitro indeed perturbed the tight junction (TJ) barrier with a concomitant decline in the production of BTB constituent proteins as follows: occludin, N-cadherin, and ZO-1. Additionally, local administration of TGF-beta3 to testes in vivo was shown to reversibly perturb the BTB integrity and Sertoli-germ cell adhesion via the p38 MAPK and ERK signaling pathways. Most importantly, the simultaneous activation of p38 and ERK signaling pathways is dependent on the association of the TGF-beta3-TbetaR1 complex with adaptors TAB1 and CD2AP because if TbetaR1 was associated preferentially with CD2AP, only Sertoli-germ cell adhesion was perturbed without compromising the BTB. Collectively, these data illustrate that local production of TGF-beta3, and perhaps other TGF-betas and cytokines, by Sertoli and germ cells into the microenvironment at the BTB during spermatogenesis transiently perturbs the BTB and Sertoli-germ cell adhesion to facilitate germ cell migration when the activated TbetaRI interacts with adaptors TAB1 and CD2AP. However, TGF-beta3 selectively disrupts Sertoli-germ cell adhesion in the seminiferous epithelium to facilitate germ cell migration without compromising BTB when TbetaRI interacts only with adaptor CD2AP.

Activin Receptors, Type I↗
PubMed2005

Transforming growth factor-beta3 promotes mesenchymal cell proliferation and angiogenesis mediated by the enhancement of cyclin D1, Flk-1, and CD31 gene expression during CL/Fr mouse lip fusion.

BACKGROUND: Cleft lip with or without cleft palate is the most common congenital anomaly in the craniofacial region. Knowledge of the molecular mechanisms behind normal lip fusion can contribute to better intervention and improved functional clinical outcome. Transforming growth factor-beta3 (TGF-beta3) has been implicated in lip morphogenesis. Therefore, we hypothesized that TGF-beta3 functions during lip fusion through regulation of angiogenesis and mesenchymal cell cycle progression during early developmental stages. METHODS: To test this hypothesis we used the CL/Fraser mouse model, which has a high incidence of cleft lip. Lips isolated from embryonic day (ED) 11.5 mouse embryos were allowed to develop in serum-free organ cultures in the presence or absence of TGF-beta3. The lips that developed in these cultures fused in 2 days. RESULTS: During normal development, we detected positive immunoreactions for TGF-beta3 at the site of fusion. We also detected mesenchymal cells that were immunopositive for Flk-1 and CD31, which are markers for endothelial cell precursors. Exogenous TGF-beta3 accelerated lip fusion in culture. This enhancement was associated with an increase in the number of capillary blood vessels in the lips cultured in the presence of TGF-beta3, in comparison with controls. In tandem, TGF-beta3 increased the level of expression of both Flk-1 and CD31. Our data suggest that an elevated level of TGF-beta3 may promote angiogenesis in developing lips that is mediated by increased Flk-1 and CD31 expression. We also detected increased cyclin D1 expression (a marker for cell proliferation) in the presence of TGF-beta3, which suggests that TGF-beta3 promoted cell proliferation. CONCLUSIONS: TGF-beta3 promoted cell proliferation and angiogenesis in lip mesenchymal tissues. These events led to enhanced lip fusion in the presence of TGF-beta3.

Animals↗
PubMed2001

Effect of antisense suppression of transforming growth factor-beta3 gene on lactotropic cell proliferation.

The mechanism by which oestrogen regulates lactotropic cell proliferation is not well understood. Recently it has been shown that a transforming growth factor beta (TGF-beta) gene-related peptide, TGF-beta3, is produced in the lactotropes and stimulates lactotropic cell proliferation in vitro. In this study, the role of this growth factor in oestrogen-induced lactotropic cell proliferation was determined in vitro using oligonucleotide designed to inhibit TGF-beta3 gene expression. We used the oligonucleotide in an antisense orientation, which is complementary to regions in the TGF-beta3 message. Oligonucleotides in sense and missense orientation were also used. We found that the antisense sequence that was effectively incorporated into pituitary cells produced a marked inhibition of the stimulatory action of oestrogen on lactotropic cell proliferation. Sense and missense oligonucleotides produced no significant effects on oestrogen-stimulated lactotropic cell proliferation. The growth-inhibitory effect of antisense oligonucleotide was blocked by TGF-beta3 peptide. These results suggest that TGF-beta3 may be involved in the processes that mediate oestrogen-regulated lactotropic cell proliferation.

Animals↗
PubMedDate not supplied

Transforming growth factor-beta3 affects plasminogen activator inhibitor-1 expression in fetal mice and modulates fibroblast-mediated collagen gel contraction.

For over two decades, the precise role of transforming growth factor-beta (TGF-beta) isoforms in scarless healing of mammalian fetal skin wounds has generated much interest. Although their exact role remains to be established, it has been suggested that high TGF-beta3 activity may correlate with a scarless phenotype. Previously, we showed that plasminogen activator inhibitor-1 (PAI-1), a known TGF-beta downstream molecule and marker of fibrosis, is also developmentally regulated during fetal skin development. In this study, the relationship between TGF-beta3 and PAI-1 was investigated using embryonic day 14.5 TGF-beta3 knockout (ko) mice. The results showed increased PAI-1 expression in the epidermis and dermis of ko mice, using an ex vivo limb-wounding study. Furthermore, increased PAI-1 expression and activity was seen in embryo extracts and conditioned media of ko dermal fibroblasts. When TGF-beta3 knockout fibroblasts were placed into three-dimensional collagen matrices, they were found to have decreased collagen gel contraction, suggesting altered cell-matrix interaction. These findings provide a further avenue for the interactive role of TGF-beta3 and PAI-1 during fetal scarless repair.

Animals↗
PubMed2005

Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous disorder characterized by fibro-fatty replacement of the right ventricular myocardium, associated with high risk of sudden death. The objective of this study is to identify the gene involved in ARVD1, which has been elusive ever since its locus was mapped to chromosome 14q24.3. METHODS AND RESULTS: Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFbeta3) gene was performed by direct sequencing of genomic DNA of one index case belonging to an ARVD1 family including 38 members in four generations. We detected a nucleotide substitution (c.-36G>A) in 5' UTR of TGFbeta3 gene, invariably associated with the typical ARVC clinical phenotype in the affected family members, according to the established diagnostic criteria. Investigation extended to 30 unrelated ARVC patients, performed by denaturing high-performance liquid chromatography (DHPLC), led to the identification of an additional mutation (c.1723C>T) in the 3' UTR of one proband. Neither nucleotide change was found in 300 control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were twofold more active than wild-types. CONCLUSION: We identified TGFbeta3 as the disease gene involved in ARVD1. The identification of a novel ARVC gene will increase the power of the genetic screening for early diagnosis of asymptomatic carriers among relatives of ARVC patients.

3' Untranslated Regions↗
PubMed2000

Transforming growth factor-beta3 stimulates lactotrope cell growth by increasing basic fibroblast growth factor from folliculo-stellate cells.

Recently, we have shown that transforming growth factor-beta3 (TGFbeta3) mediates estradiol's mitogenic action in primary cultures of mixed anterior pituitary cells. In some cell types, TGFbeta isoforms stimulate cell proliferation via a paracrine mechanism by increasing growth stimulatory peptide growth factors. Whether such a mechanism exists in pituitary cell culture was examined in the studies presented here. The data demonstrate that unlike the response of lactotropes in mixed pituitary cultures, cultures of enriched lactotropes, obtained by Percoll gradient separation, did not proliferate in response to TGFbeta3 treatment. The lactotropic cells of the RC-4B/C cell line, a cell line that contains all of the hormone-secreting cell types of the anterior pituitary but is devoid of folliculo-stellate (FS) cells, did not proliferate in response to TGFbeta3 unless RC-4B/C cells were cocultured with FS cells. Enriched lactotropes cocultured with FS cells also demonstrated a proliferative response to TGFbeta3. Media collected from FS cells treated with TGFbeta3 stimulated the proliferation of lactotropes in enriched cultures. TGFbeta3 increased the release of basic fibroblast growth factor from FS cells. Immunoneutralization of basic fibroblast growth factor in FS cell-conditioned medium inhibited the growth stimulatory action on lactotropes. These data provide evidence for a novel mechanism of TGFbeta3 action involving cell-to-cell interaction in the anterior pituitary between lactotropes and FS cells during estrogen-induced mitogenesis.

Animals↗
PubMed2006

Bisphenol A induces transforming growth factor-beta3 mRNA in the preoptic area: a cDNA expression array and Northern blot study.

To gain better understanding of the effects of bisphenol A (BPA) in the adult brain, a cDNA expression array was used to screen possible candidates for BPA-inducible genes in the medial preoptic area (MPOA). Adult ovariectomized rats were given a subcutaneous injection of 10 mg BPA or sesame oil alone as a control. Twenty-four hours after the injection, the MPOAs were dissected and total RNAs were extracted. When expression levels of cDNAs derived from pooled samples were compared to controls, the expression levels of some genes in BPA-injected rats appeared to be different from those in sesame oil-injected rats. Among the candidate genes, we focused on an increase in the expression of transforming growth factor (TGF)-beta3 mRNA. To quantify the change in TGF-beta3 mRNA by BPA, we examined the effects of 10 mg BPA (n=6), 1 microg 17beta-estradiol (n=6), or oil injection (n=6) on the expression of TGF-beta3 mRNA in the MPOA of ovariectomized rats by Northern blot. The TGF-beta3 mRNA level in the MPOA of BPA-injected rats was significantly increased compared to the level in oil-injected rats (p<0.05). Injection of 1 microg 17beta-estradiol did not have any significant effect. The results suggest that, in the adult female rat, BPA acts on the MPOA by altering the expression of the TGF-beta3 gene in a manner distinct from that of estrogen.

Animals↗
PubMed2006

Dose- and time-dependent effects of cyclic hydrostatic pressure on transforming growth factor-beta3-induced chondrogenesis by adult human mesenchymal stem cells in vitro.

This study examined effects of varying magnitudes of intermittent hydrostatic pressure (IHP) applied for different times on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. hMSCs were exposed to 0.1, 1, and 10 MPa of IHP at a frequency of 1 Hz for 4 h/day for 3, 7, and 14 days in the presence of transforming growth factor (TGF-beta3). Chondrogenesis was characterized by gene expression, macromolecule production, and extracellular matrix deposition. Exposure of hMSCs to 0.1 MPa of IHP increased SOX9 and aggrecan mRNA expression by 2.2- and 5.6-fold, respectively, whereas type II collagen mRNA expression responded maximally at 10 MPa. Production of sulfated glycosaminoglycan responded to IHP of 1 MPa and 10 MPa, whereas collagen levels increased only at 10 MPa. Morphologically, matrix condensation occurred with increased IHP, concomitant with collagen expression. This study demonstrated that different levels of IHP differentially modulate hMSC chondrogenesis in the presence of TGF-beta3. The data suggest that tissue engineering of articular cartilage through application or recruitment of hMSCs can be facilitated by mechanical stimulation.

Adult↗
PubMed2005

Role of protein kinase C-Ras-MAPK p44/42 in ethanol and transforming growth factor-beta3-induced basic fibroblast growth factor release from folliculostellate cells.

In the present study, we determined the interactive effects of ethanol and transforming growth factor beta-3 (TGF-beta3) on basic fibroblast growth factor (bFGF) release from folliculostellate (FS) cells and the role of the mitogen-activated protein kinase (MAPK) pathway in this interaction. We found that TGF-beta3 and ethanol alone increased release of bFGF from FS cells, but together they showed markedly increased levels of bFGF compared with the individual effect. Ethanol and TGF-beta3 alone moderately increased activation of MAPK p44/42, but together they produced marked activation of MAPK p44/42. TGF-beta3 alone increased the activation of smad2. Ethanol did not activate smad2 or alter TGF-beta3 activation of smad2. Pretreatment of FS cells with a mitogen-activated protein kinase kinase 1/2 inhibitor or with a protein kinase C (PKC) inhibitor suppressed the TGF-beta3 and ethanol actions on MAPK p44/42 activation and bFGF release. Ethanol and TGF-beta3, either alone or in combination, increased the levels of active Ras. Furthermore, the MAPK p44/42 activation by TGF-beta3 and ethanol was blocked by overexpression of Ras N17, a dominant negative mutant of Ras p21. These data suggest that the PKC-activated Ras-dependent MAPK p44/42 pathway is involved in the cross talk between TGF-beta3 and ethanol to increase bFGF release from FS cells.

Animals↗
PubMed2003

Transforming growth factor-beta3 gene SfaN1 polymorphism in Korean nonsyndromic cleft lip and palate patients.

The nonsyndromic cleft lip and palate (NSCL/P) is a congenital deformity of multifactorial origin with a relatively high incidence in the oriental population. Various etiologic candidate genes have been reported with conflicting results, according to race and analysis methods. Recently, the ablation of the TGF-beta3 gene function induced cleft palates in experimental animals. Also, polymorphisms in the TGF-beta3 gene have been studied in different races; however, they have not been studied in Koreans. A novel A --> G single nucleotide polymorphism (defined by the endonuclease SfaN1) was identified in intron 5 of TGF-beta3 (IVS5+104 A > G). It resulted in different genotypes, AA, AG, and GG. The objective of this study was to investigate the relationship between the SfaN1 polymorphism in TGF-beta3 and the risk of NSCL/P in the Korean population. The population of this study consisted of 28 NSCL/P patients and 41 healthy controls. The distribution of the SfaN1 genotypes was different between the cases and controls. The frequency of the G allele was significantly associated with the increased risk of NSCL/P [odds ratio (OR) = 15.92, 95% confidence interval (CI) = 6.3-41.0]. The risk for the disease increased as the G allele numbers increased (GA genotype: OR = 2.11, 95% CI = 0.38-11.68; GG genotype: OR = 110.2, 95% CI = 10.67 - 2783.29) in NSCL/P. A stratified study in patients revealed that the SfaN1 site IVS5+104A > G substitution was strongly associated with an increased risk of NSCL/P in males (p < 0.001), but not in females. In conclusion, the polymorphism of the SfaN1 site in TGF-beta3 was significantly different between the NSCL/P patients and the control. This may be a good screening marker for NSCL/P patients among Koreans.

Base Sequence↗
PubMed2003

The roles of transforming growth factor type beta3 (TGF-beta3) and mast cells in the pathogenesis of scleroderma.

Scleroderma is a connective tissue disorder characterised by excessive accumulation of collagen in the skin and internal organs. The most likely explanation for this process is local activation of collagen synthesis from fibroblasts. Our intention was to elucidate whether TGF-beta3 and mast cells play a pathogenic role in abnormal connective tissue formation in scleroderma. In this study, skin biopsies from 20 patients with scleroderma and five from healthy individuals were studied by an indirect immunoperoxidase technique to determine the immunoreactivity of TGF-beta3 in the dermis. In addition, skin samples were stained with toluidine blue to count the number of mast cells in scleroderma, and tissues were examined under the electron microscope to evaluate the ultrastructural changes. Increased TGF-beta3 immunoreactivities were detected in the dermis in the patient's skin, suggesting the presence of a subpopulation responsible for the increased collagen production. Mast cell counts in the skin of patients with scleroderma were significantly greater (19.2 +/- 4.1/unit) than those of normal controls (4.4 +/- 1.2/unit). Ultrastructural observations indicated that there is a close relationship between the mast cells and fibroblasts. These results suggest that fibrosis in scleroderma could evolve through the activation of fibroblasts and the regulatory mechanisms that appear to modulate the behavior of these cells with respect to collagen production.

Adult↗
PubMed2004

Hypoxia-inducible factor-1 transactivates transforming growth factor-beta3 in trophoblast.

Hypoxia occurs during the development of placenta in the first trimester and is implicated in trophoblast differentiation. Intervillous blood flow increases after 10 wk of gestation and results in exposure of trophoblast cells to oxygen. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. The oxygen-regulated early events of trophoblast differentiation are mediated by TGF-beta3. TGF-beta3 plays a vital role in trophoblast differentiation, and its overexpression can be found in preeclamptic placenta. We sought to determine the mechanism of TGF-beta3 expression through hypoxia-inducible factor (HIF)-1. We show that HIF-1alpha and TGF-beta3 are overexpressed in preeclamptic placenta. Hypoxia not only transactivates the TGF-beta3 promoter activity but also enhances endogenous TGF-beta3 expression. Using the TGF-beta3 promoter deletion mutants, we show that the region between -90 and -60, which contains a putative HIF-1 consensus motif, is crucial for HIF-1-mediated transactivation. Electrophoretic mobility shift assays show that HIF-1 binds to the oligonucleotide containing the HIF-1 motif. Also, introduction of an antisense oligonucleotide for HIF-1 diminishes TGF-beta3 expression during hypoxia, indicating that the up-regulation of TGF-beta3 by hypoxia is mediated through HIF-1. Our results provide evidence that regulation of TGF-beta3 promoter activity by HIF-1 represents a mechanism for trophoblast differentiation during hypoxia.

Cell Line, Tumor↗
PubMed2003

Involvement of protein kinase C-dependent mitogen-activated protein kinase p44/42 signaling pathway for cross-talk between estradiol and transforming growth factor-beta3 in increasing basic fibroblast growth factor in folliculostellate cells.

We have recently shown that TGF-beta3, in the presence of estradiol, increases the release of basic fibroblast growth factor (bFGF) from folliculostellate (FS) cells in the pituitary. We determined the interactive effects of TGF-beta3 and estradiol on bFGF production and release from FS cells, and the role of the MAPK pathway in TGF-beta3 and estradiol interaction. We found that TGF-beta3 and estradiol alone moderately increased cell content and release of bFGF from FS cells; but together, they markedly increased the peptide. Estradiol and TGF-beta3 alone moderately activated MAPK p44/42; together they produced marked activation of MAPK p44/42. Pretreatment of FS cells with an MAPK kinase 1/2 inhibitor or with protein kinase C inhibitors suppressed the activation of MAPK p44/42, bFGF release, and protein level increases, all of which were induced by TGF-beta3 and estradiol. Estradiol and TGF-beta3, either alone or in combination, increased the levels of active Ras. Furthermore, bFGF induction by TGF-beta3 and estradiol was blocked by overexpression of Ras N17, a dominant negative mutant of Ras p21. Estrogen receptor blocker ICI 182,780 failed to prevent estrogen's and TGF-beta3's effects on bFGF. These data suggest that an estradiol receptor-independent protein kinase C- activated Ras-dependent MAPK pathway is involved in the cross-talk between TGF-beta3 and estradiol to increase bFGF production and/or release from FS cells.

Animals↗