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Results for “Transforming Growth Factor beta2”

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PubMed1997

Isolation of transforming growth factor-beta2 cDNA from a fish, Cyprinus carpio by RT-PCR.

Transforming Growth Factors-beta (TGF-betas) have been described in many vertebrate species of amphibians, aves and mammals. In this report we demonstrate the presence of TGF-beta2 in pisces. TGF-beta2 has been cloned from a fish, Cyprinus carpio, by RT-PCR using degenerate oligonucleotide primers. Sequence analysis of the amplified product and alignment of the deduced amino acid sequence with the human TGF-beta2 amino acid sequence revealed 81% and 93% identity in the precursor and the mature regions, respectively. The northern blot analysis of fish heart RNA shows a major messenger RNA species of about 8.0 kb and two messages of very low abundance of about 5.0 kb and 4.0 kb. The identification of TGF-beta2 isoform in Pisces and it's high degree of homology with the mammalian isoform suggests that among all TGF-beta isoforms, TGF-beta2 is the most conserved during evolution.

Amino Acid Sequence↗

PubMed2004

[The effect of montelukast on airway remodeling and the expression of interleukins and transforming growth factor-beta2 mRNA].

OBJECTIVE: To study the relation between Interleukin-4 (IL-4), IL-5, IL-13, transforming growth factor-beta(2) (TGF-beta(2)) and airway remodeling and to investigate the effects of Montelukast (MK) on airway inflammation and airway remodeling of asthma. METHODS: Twenty female BALB/c mice were randomly divided into a remodeling group and a treatment group (MK group), with 10 BALB/c mice in each group. The mice were sensitized by ovalbumin (OVA), and only the MK group was treated with MK (15 mg/kg). The number of total cells and eosinophils in bronchoalveolar lavage fluid (BALF) were counted. Light and electronic microscope were used to detect the pathologic histology and morphologic change. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) were used to measure IL-4, L-5, IL-13, and TGF-beta(2) mRNAs in the lung. RESULTS: The numbers of total cells and eosinophils in BALF of the remodeling group were (5.4 +/- 1.1) x 10(5)/ml and 2.32 +/- 0.20, while those of the treatment group were (3.9 +/- 1.6) x 10(5)/ml and 1.64 +/- 0.32, respectively, the difference being significant (P < 0.01). Histological and electronic microscopic examination showed extensive airway inflammation, notably accumulation of significant numbers of eosinophils and lymphocytes in the remodeling group. Other features including prominent proliferation of airway epithelial cells protruded like fingers, increased thickness of smooth muscle, hyperplasia of connective tissue, goblet cell hyperplasia and a marked increase in airway mucus secretion with mucus plugging and extensive collagen deposition around the airways were also noted in the remodeling group. In the treatment group, the inflammation was significantly decreased, with decreased production of mucus, decreased collagen and granule of mucus around airway, less proliferation of airway epithelium, smooth muscle hypertrophy and airway spasm. In situ hybridization showed that the expression of IL-13 mRNA and TGF-beta(2) mRNA in the lung of the remodeling group were 24 +/- 7 and 17 +/- 5 respectively, while those of the treatment group were 17 +/- 4 and 10 +/- 3. RT-PCR results showed that the absorbance of IL-4 mRNA and IL-5 mRNA in the lung of the remodeling group were 0.91 and 0.96, while those of the treatment group were 0.22 and 0.35; the differences between the groups were all significant (all P < 0.01). CONCLUSION: MK could effectively inhibit airway remodeling, which suggests a possible role of cysteinyl leukotrienes in the pathogenesis of chronic allergic inflammation with fibrosis.

Acetates↗

PubMed2001

Isolation and characterization of the murine transforming growth factor-beta2 promoter.

This report describes the isolation and characterization of the 5' flanking region of the murine transforming growth factor beta-2 (TGF-beta2) gene. A genomic clone containing the promoter region of the gene was isolated after screening a bacteriophage P1 genomic library. The resulting clone was sequenced and compared to promoters for the human and chicken TGF-beta2 genes. The sequence located near the transcription start site is highly conserved. It includes a TATA box, an E-box, and a largely conserved CRE/ATF site. A series of murine TGF-beta2 promoter/reporter constructs was generated to identify regulatory regions of the gene. As in the case of the human TGF-beta2 gene, sequences just upstream of the TATA box, including the CRE/ATF site, actively stimulate the murine TGF-beta2 promoter. However, unlike the human TGF-beta2 gene, the 5' flanking region of the murine TGF-beta2 gene contains a long alternating purine/pyrimidine repeat that unexpectedly exerts a strong positive effect on its promoter. This is of particular interest since alternating purine/pyrimidine repeats in other promoters have been observed to be inhibitory.

Animals↗

PubMed1996

Transforming growth factor-beta2 increases NMDA receptor-mediated excitotoxicity in rat cerebral cortical neurons independently of glia.

The ability of transforming growth factor-beta2 (TGFbeta2) to directly regulate neuronal sensitivity to glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity in rat cerebral cortical neurons was investigated. Mixed neuronal-glial cultures treated with TGFbeta2 (1-10 ng/ml) exhibited a significant 25-50% increase in neuronal death compared to control cultures. TGFbeta2 potentiation of this endogenous glutamate excitotoxicity was blocked by the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate. In addition, neuronal death induced by brief NMDA exposure in both mixed neuronal-glial and pure neuronal cultures was increased by TGFbeta2 (1-30 ng/ml) with a similar dose-response curve. These findings indicate that TGFbeta2, at physiologically relevant concentrations, potentiates NMDA receptor-mediated excitotoxicity and that this occurs independently of TGFbeta2 effects on glia.

2-Amino-5-phosphonovalerate↗

PubMed2003

Circulating levels of osteoclast activating cytokines, interleukin-11 and transforming growth factor-beta2, as valuable biomarkers for the assessment of bone turnover in postmenopausal osteoporosis.

The objective of this study was to evaluate the role of osteoclast activating cytokines, interleukin-11 (IL-11) and transforming growth factor-beta2 (TGF-beta2) in the assessment of bone turnover in postmenopausal osteoporosis (PO). Eighty postmenopausal osteoporotic women with lumbar spine bone mineral densities (BMD) as measured by DEXA that were more than 2.5 SD below the normal mean of healthy women (controls), participated in this study. Various therapeutic modalities (hormone replacement therapy, HRT, alendronate, calcitonin and 1alpha-hydroxyvitamin D (alfacalcidol) were administered for 12 months to 4 groups of postmenopausal osteoporotic patients. Fasting blood samples and two hour urine samples were collected from control subjects and from patients before and after treatment. Serum samples were assayed for IL-11, TGF-beta2, osteocalcin (OC) and bone alkaline phosphatase (B-ALP), whereas urine samples were assayed for N-telopeptide for type I collagen (NTX) and deoxypyridinoline (DPyr). The results demonstrated a significant increase of both IL-11 and TGF-beta2 in postmenopausal osteoporosis. Positive correlations exist between TGF-beta2 or IL-11 and markers of bone resorption (NTX and DPyr). Moreover, there was a significant positive correlation between TGF-beta2 and IL-11. Therapeutic modalities enhancing bone formation and/or with antiresorptive effect revealed a significant decrease in markers of bone resorption, formation and osteoclast activating cytokines, indicating a decrease in bone turnover. The decrease of IL-11 and TGF-beta2 may be attributed to a drug inhibitory effect of these cytokines on enhancing osteoblast mediated osteoid degradation. In conclusion, both serum IL-11 and TGF-beta2 determinations may be considered as biomarkers for the assessment of bone turnover and for monitoring antiresorptive therapy in postmenopausal osteoporosis.

Adult↗

PubMed2002

Differential effects of transforming growth factor-beta2 on corneal endothelial cell proliferation-A role of serum factors.

PURPOSE: To determine the influence of serum on transforming growth factor (TGF)-beta2 mediated effects on the proliferation of corneal endothelial cells (CE). METHODS: Rat CE were grown in explant culture and the proliferation of CE was measured by [(3)H]thymidine bioassay. Subconfluent cells were synchronized in the G0 (quiescent) phase of the cell cycle by serum starvation for 24hr. Serum and [(3)H]thymidine were then added to the cells in the presence or absence of a physiological concentration (5ngml(-1)) of exogenous active TGF-beta2. Radioactivity was measured at various time points to detect DNA synthesis. These experiments were repeated without adding serum after serum starvation. Preincubation of exogenous TGF-beta2 with neutralizing antibody was used to test the cytokine specificity. RESULTS: Without TGF-beta2, a linear increase in [(3)H]thymidine incorporation, indicating S-phase, began approximately 16hr after serum addition, then plateaued at approximately 24hr. Serum promoted DNA synthesis of CE in a dose-dependent manner at concentrations of 0.5-10%. In cultures with 10% serum, TGF-beta2 (0.5, 1, 5, and 20ngml(-1)) suppressed CE growth dose-dependently. The growth amplitude decreased and the time before S-phase entry, G1 phase, was prolonged to 24hr. In culture with 1% serum, TGF-beta2 (5ngml(-1)) suppressed the CE proliferation by delaying S-phase entry without suppressing growth amplitude. In cultures without serum, TGF-beta2 promoted CE growth to a level similar to that of cultures supplemented with 0.5% serum. CONCLUSIONS: Responses of cultured CE to exogenous TGF-beta2 depended on the concentration of serum in the medium. This result implies a possibility that in vivo serum influx through a compromised blood-ocular barrier could influence the CE growth by changing the responses of these cells to TGF-beta2 in aqueous humor.

Animals↗

PubMed2002

Circadian variations of transforming growth factor-beta2 and basic fibroblast growth factor in the rabbit aqueous humor.

PURPOSE: To compare levels of transforming growth factor-beta2 (TGF-beta2) and basic fibroblast growth factor (bFGF) in the ocular fluids of rabbits at various times of the day. METHODS: Seventy-two young adult New Zealand albino rabbits were entrained to a daily 12-hour light (6 AM to 6 PM) and 12-hour dark cycle. Eight rabbits were sacrificed at each of 6 time points: 4 AM, 8 AM, noon, 4 PM, 8 PM, and midnight. Under an acute 24-hour constant dark condition, 8 additional rabbits were sacrificed at each of 3 time points in the accustomed light period (8 AM, noon, and 4 PM). Samples of aqueous humor and vitreous humor were collected from both eyes. Using enzyme immunoassay, samples from one eye were assayed for total TGF-beta2 and active form of TGF-beta2 and samples from the other eye were assayed for bFGF. Concentrations at various time points were analyzed using one-way ANOVA and post-hoc Bonferroni t-test for multiple comparisons. RESULTS: Aqueous humor levels of total TGF-beta2, active TGF-beta2, and bFGF changed during the 24-hour period. Total TGF-beta2 and bFGF levels increased between 4 AM and 8 AM. Active TGF-beta2 level increased between 8 PM and midnight. Similar patterns of changes were found when considering aqueous humor samples collected under the acute constant dark condition. In the vitreous humor, total TGF-beta2, active TGF-beta2, and bFGF remained unchanged throughout the 24 hours. CONCLUSIONS: Endogenous circadian rhythms of total TGF-beta2, active TGF-beta2, and bFGF occur in the rabbit aqueous humor. These two extracellular signaling molecules may be associated with specific physiological functions in the anterior segment according to the time of the day.

Animals↗

PubMed2007

Downregulation of transforming growth factor-beta2 facilitates inflammation in the central nervous system by reciprocal astrocyte/microglia interactions.

The central nervous system is an immune privileged organ in which inflammatory reactions are normally downregulated by mechanisms that are not completely understood. Transforming growth factor (TGF)-beta2 is constitutively expressed in the adult central nervous system and little is known about its regulation and modulatory role during neuroinflammation. In this study, we show that TGFbeta2 mRNA and protein are downregulated in the acute phase of chronic relapsing experimental autoimmune encephalomyelitis, whereas the homologous cytokine TGFbeta1 is upregulated. To further characterize regulatory mechanisms, we resorted to an in vitro glial cell culture system. The proinflammatory cytokines IFNgamma and TNFalpha suppressed TGFbeta2 secretion by astrocytes, the major intracerebral producers of TGFbeta2. On the cellular level, activated microglia inhibited TGFbeta2 secretion but induced TGFbeta1 through soluble factors. On the other hand, TGFbeta2 influenced antigen-presenting cell functions of microglia by downregulating major histocompatibility complex class II expression and costimulatory/adhesion molecules, and thereby inhibited myelin basic protein-specific T cell proliferation. These data suggest that TGFbeta2 plays a central role in maintenance of the immune privilege of the central nervous system. Downregulation of astrocytic TGFbeta2 by T cell- and microglia-secreted cytokines appears to be a critical step in providing the grounds for acute and chronic neuroinflammation.

Animals↗

PubMed2000

Activation of ionotropic glutamate receptors reduces the production of transforming growth factor-beta2 by developing neurons.

Neuronal cultures derived from developing rat cerebral cortex were used to investigate the influence of glutamate receptors on the neuronal production of transforming growth factor-beta2 (TGFbeta2), a multifunctional cytokine that modulates neuronal and glial growth. Long-term exposure (48 h) of cortical neurons to selective antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors markedly increased TGFbeta2 levels in the culture medium. Conversely, treatment with NMDA or kainate reduced TGFbeta2 to levels below those in untreated cultures. The effect of kainate did not require NMDA receptor activity. Neuronal depolarization with K+ also reduced TGFbeta2 levels by opening voltage-gated L-type Ca2+ channels. Semi-quantitative RT-PCR measurements of neuronal TGFbeta2 mRNA showed that NMDA or AMPA/kainate receptor stimulation reduced TGFbeta2 mRNA levels. These results demonstrate that tonic activation of glutamate-gated cation channels downregulates neuronal expression of the TGFbeta2 gene and provide evidence for a novel mechanism whereby excitatory amino acids could influence the development of glial and neuronal lineages.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

The effects of transforming growth factor-beta2 on dopaminergic graft survival.

Dopaminergic cell transplantation is a promising therapeutic approach for the treatment of Parkinson's disease, the potential of which is limited due to poor survival and low dopamine content within engrafted tissue. In this study, the ability of transforming growth factor-beta2 (TGF-beta2) to influence transplant survival was evaluated. Cell suspensions containing fetal rat ventral mesencephalon (VM) cells were incubated prior to surgery with vehicle (DPBS), varying concentrations of TGF-beta2 (5-1000 ng/ml), or a pan-specific antibody against TGF-beta (1D11, 100 ng/ml). VM cell suspensions (200,000 cells) were unilaterally implanted into the striatum of adult Sprague-Dawley rats (n = 5-11 animals/group). Following a 3-week survival period, small but viable VM grafts containing tyrosine hydroxylase-positive (TH+) neurons and fibers were present in all animals. Addition of TGF-beta2 resulted in a steep, bell-shaped dose-response curve with a significant effect on TH+/dopamine cell survival. At 50 ng/ml TGF-beta2, the number of surviving dopamine neurons was increased twofold compared with controls. Addition of TGF-beta2 or 1D11 did not significantly influence graft volume. Further studies, possibly in combination with other neurotrophic factors, need to be performed to obtain a greater understanding of the effects of TGF-beta on dopamine neurons and fetal VM cell engraftment.

Animals↗

PubMed1996

Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells.

Retinoic acid (RA) is a potent in vitro inhibitor of cell proliferation in various malignant cell lines. The exact mechanisms of its actions, however, are not fully understood. To further elucidate the nature of this inhibition, we investigated the effects of RA in an estrogen receptor-negative human breast cancer cell line, MDA-MB-231. RA (0.01-5 microM) significantly inhibited MDA-MB-231 cell growth by 35-40% as compared with untreated controls. Similar growth inhibitory actions were observed when cells were treated with transforming growth factor beta2 (TGF-beta2), another factor with antiproliferative actions in breast cancer cells. Both RA and TGF-beta2 increased the levels of insulin-like growth factor binding protein (IGFBP) 3 (2-3-fold) and mRNA (1.5-2-fold), whereas IGFBP-4 levels remained essentially unchanged. The direct involvement of IGFBP-3 in cell growth inhibition was further confirmed by its action on cell growth: exogenous IGFBP-3 directly and significantly inhibited MDA-MB-231 cell number by 40%. These results provided circumstantial evidence that IGFBP-3 may mediate RA and TGF-beta2 growth inhibitory actions in human breast cancer cells. To test this hypothesis, we used an antisense IGFBP-3 oligodeoxynucleotide (ODN) which specifically inhibits IGFBP-3 expression. The antisense IGBP-3 ODN dramatically blocked both RA- and TGF-beta2-induced increases in IGFBP-3 protein (90%) and mRNA levels (90%). This effect was not observed when RA- or TGF-beta2-exposed cells were treated with sense IGFBP-3 ODN. Moreover, antisense ODN did not significantly affect IGFBP-4 protein or mRNA levels, strongly supporting the specificity of the antisense IGFBP-3 ODN effect on IGFBP-3 mRNA. This specific effect of antisense IGFBP-3 ODN on IGFBP-3 protein and mRNA levels was accompanied by significant attenuation of the inhibition of cell proliferation attained with RA or TGF-beta2 (approximately 40% of either RA- or TGF-beta2-induced inhibition). The control sense IGFBP-3 ODN did not reduce the growth inhibition observed with either RA or TGF-beta2. These results indicate that IGFBP-3 is an important mediator of RA- and TGF-beta2-induced cell growth inhibition in human breast cancer cells.

Base Sequence↗

PubMed2005

Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution.

The mechanisms regulating thymic involution are unclear. In inbred mouse strains the rate of thymic involution and the function of the hematopoietic stem cell (HSC) compartment are subject to quantitative genetic variation. We have shown previously that transforming growth factor-beta2 (TGF-beta2) is a genetically determined positive regulator of HSCs. Here, we demonstrate that genetic variation in the rate of thymic involution correlates with genetic variation in the responsiveness of hematopoietic stem and progenitor cells to TGF-beta2. Corroborating these correlations, thymic cellularity and peripheral naive T-cell frequency were higher in old Tgfb2+/- mice than in wild-type littermates. The frequency of early T-cell precursors was increased in Tgfb2+/- mice, suggesting that TGF-beta2 affects the earliest stages of T-cell development in old mice. Reciprocal transplantation experiments indicated that TGF-beta2 expressed both in the (micro)environment and in the hematopoietic system can accelerate thymic involution; however, the age of the stem cells appeared irrelevant. Thus, although thymic involution is largely determined by the aged environment, TGF-beta2 plays a major modulatory role that is subject to genetic variation and is possibly mediated through its regulatory effects on early hematopoiesis.

Aging↗

PubMed2001

Response to hypoxia involves transforming growth factor-beta2 and Smad proteins in human endothelial cells.

Oxygen deprivation (hypoxia) is a consistent component of ischemia that induces an inflammatory and prothrombotic response in the endothelium. In this report, it is demonstrated that exposure of endothelial cells to hypoxia (1% O(2)) increases messenger RNA and protein levels of transforming growth factor-beta2 (TGF-beta2), a cytokine with potent regulatory effects on vascular inflammatory responses. Messenger RNA levels of the TGF-beta2 type II membrane receptor, which is a serine threonine kinase, also increased. The stimulatory effect of hypoxia was found to occur at the level of transcription of the TGF-beta2 gene and involves Smad proteins, a class of intracellular signaling proteins that mediates the downstream effects of TGF-beta receptors. Transient transfection studies showed that the region spanning -77 and -40 base pairs within the TGF-beta2 promoter (harboring a Smad-binding "CAGA box") is activated in hypoxic cells compared with nonhypoxic controls (P <.01). Hypoxia also stimulated transcription from another promoter, 3TP-Lux, a reporter construct responsive to Smads and TGF-beta. In addition, specific binding to a Smad-binding oligonucleotide was observed with nuclear extracts from hypoxic endothelial cells but not from nonhypoxic cells. It is concluded that Smad proteins, which can regulate endothelial responses to mechanical and inflammatory stress, also may play an important role in vascular responses to hypoxia and ischemia.

Binding Sites↗

PubMed2005

High-density lipoproteins induce transforming growth factor-beta2 expression in endothelial cells.

BACKGROUND: HDL is endowed with cardiovascular protective activities. In addition to its role in reverse cholesterol transport, HDL influences different functions of endothelial cells. In the present study, we investigated in endothelial cells the genes involved in inflammation modulated by HDL. METHODS AND RESULTS: Through cDNA array analysis, transforming growth factor (TGF)-beta2 appeared to be a gene responsive to HDL treatment in endothelial cells. Quantitative real-time polymerase chain reaction confirmed that HDL subfraction 3 selectively induces TGF-beta2 mRNA expression and protein release, whereas TGF-beta1 and TGF-beta3 were not affected. This effect was mainly PI3K/Akt dependent. Lysosphingolipids present in HDL such as sphingosine 1 phosphate and sphingosylphosphorylcholine mimicked the effects of the whole HDL. These results were confirmed in vivo in transgenic mice overexpressing human apolipoprotein (apo) A-I. Compared with apoA-I-knockout mice, phospho-Akt, phospho-ERK1/2, and TGF-beta2 expression was increased in the aorta of transgenic mice overexpressing human apoA-I. In addition, the expression of phospho-Smad2/3, the transcription factor activated by TGF-beta, is increased in transgenic mice compared with knockout mice. CONCLUSIONS: Because TGF-beta possesses antiinflammatory properties and stabilizes the plaque, the results of the present work suggest a novel target for the antiatherosclerotic effect of HDL.

Animals↗

PubMedDate not supplied

Transforming growth factor-beta2 (TGF-beta2) reverses the inhibitory effects of fibrin sealant on cutaneous wound repair in the pig.

Tensile strength of 2-cm, full-thickness, surgically incised porcine skin wounds sealed with fibrin sealant was enhanced compared to conventionally sutured wounds at 6 hours postwounding, but was significantly reduced after 3 days. Supplementation of fibrin sealant with transforming growth factor-beta2 (TGF-beta2) reversed the inhibitory effects of fibrin sealant on tensile strength at 3 days, and enhanced tensile strength at 7 days compared to suture or fibrin sealant alone. By 14 days, the tensile strengths of all wounds were similar, although wounds treated with fibrin sealant supplemented with TGF-beta2 showed a small, but statistically significant, improvement in wound strength compared to wounds treated with fibrin sealant alone. Histological assessment at day 7 revealed significant remnants of fibrin sealant at the wound site following fibrin sealant treatment alone, while wounds treated with fibrin sealant supplemented with TGF-beta2 or suture exhibited fibroblast infiltration and extracellular matrix deposition. At day 7, TGF-beta was immunolocalized in the base and margins of only wounds treated with fibrin sealant supplemented with TGF-beta2. A significant increase in matrix metalloproteinase-9 activity was found in fibrin sealant-treated wounds at day 7 as compared to sutured wounds. Addition of TGF-beta to the fibrin sealant suppressed the up-regulation of matrix metalloproteinase-9 in these wounds. These results suggest that fibrin sealant supplemented with TGF-beta may provide superior wound healing as compared to fibrin sealant alone.

Animals↗

PubMed1996

Transcription of the transforming growth factor-beta2 gene is dependent on an E-box located between an essential cAMP response element/activating transcription factor motif and the TATA box of the gene.

Transforming growth factor-beta2 (TGF-beta2) is an important regulator of cell proliferation and differentiation; however, its transcriptional regulation is not well understood. Here we report characterization of an essential E-box motif, positioned at -50/-45 between a previously described functional cAMP response element/activating transcription factor site and the TATA box of the human TGF-beta2 promoter. By site-directed mutagenesis, we demonstrate that this E-box motif is necessary for the promoter activity, not only in differentiated cells derived from embryonal carcinoma cells, but also in choriocarcinoma cells and in MCF-7 breast carcinoma cells. We also demonstrate that the transcription factors USF1 and USF2 bind to this E-box motif in vitro when nuclear extracts from each of these cell lines are examined by gel retardation assays. Moreover, using a dominant-negative USF2 protein, we show that USF proteins are critical for TGF-beta2 promoter activity in vivo. The importance of the E-box motif described in this study is supported by the presence of an E-box motif in the same position in the chicken TGF-beta2 gene promoter.

Cell Line↗

PubMed2004

[Influence of transforming growth factor-beta2 on production of tumor necrosis factor-alpha and interferon-gamma from placenta of intrahepatic cholestasis of pregnancy].

OBJECTIVE: To investigate the influence of transforming growth factor-beta2 (TGF-beta2) on production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) from placenta of patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: Villous explants from 10 ICP patients (ICP group) and 10 normal gravidae (control group) were cultured in vitro. The concentrations of TNF-alpha and IFN-gamma in the culture medium were determined by enzyme linked immunoadsorbent assay (ELISA) after incubation with different concentrations of TGF-beta2 for 1, 24 and 48 hours. RESULTS: (1) After cultured for 1, 24 and 48 hours, TNF-alpha level in ICP group was (771 +/- 187) pg/g, (2 490 +/- 575) pg/g, and (3339 +/- 1106) pg/g, respectively, while IFN-gamma level was (931 +/- 148) pg/g, (1888 +/- 545) pg/g, and (3027 +/- 667) pg/g, respectively. All were significantly higher than those in the normal group (P < 0.001). (2) TGF-beta2 could inhibit the release of above cytokines in a time- and dose-dependent manner: TNF-alpha level was (2490 +/- 575) pg/g, (1806 +/- 502) pg/g, and (1231 +/- 238) pg/g after 24 h, (3339 +/- 1106) pg/g, (2168 +/- 794) pg/g, and (1047 +/- 183) pg/g after 48 h, respectively; IFN-gamma level was (1888 +/- 545) pg/g, (1 347 +/- 405) pg/g, and (913 +/- 303) pg/g after 24 h, and (3027 +/- 667) pg/g, (2062 +/- 795) pg/g, and (1001 +/- 301) pg/g after 48 h, respectively. CONCLUSION: (1) The excessive production of TH1 type cytokines TNF-alpha and IFN-gamma may involve in the pathogenesis of ICP; (2) TGF-beta2 may exert immunoprotection effect through inhibiting the production of TNF-alpha and IFN-gamma.

Adult↗

PubMed2006

Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2.

In situ analysis of fetal semilunar valve leaflets has revealed cells coexpressing endothelial and mesenchymal markers along the endothelium, with diminished frequency seen in adult valves. To determine whether such cells are progenitor cells, we isolated clonal populations from human pulmonary valves. The clones expressed endothelial markers but showed potential to further differentiate into endothelium in response to vascular endothelial growth factor (VEGF)-A. When exposed to transforming growth factor (TGF)-beta2, individual clones adopted a mesenchymal phenotype to varying degrees and expressed markers of endothelial to mesenchymal transformation (EMT). Both VEGF- and TGFbeta2-induced phenotypic changes were partially reversible, indicating the plasticity of these cells. When challenged with VEGF or TGFbeta2, a hierarchy of endothelial/mesenchymal potential could be seen among the clonal populations: cells initially closer to an endothelial phenotype showed a strong response to TGFbeta2 that could be inhibited by VEGF, whereas cells closer to a mesenchymal phenotype responded to TGFbeta2 but were resistant to endothelial-inducing effects of VEGF. These findings suggest the presence of bipotential valve progenitor cells with ability to differentiate into either endothelial or interstitial cells of the valve leaflet. Understanding the differentiation potential and function of these cells may be important for understanding heart valve disease and may also be applied to current paradigms for creating tissue-engineered heart valves.

Biomarkers↗