TGF-beta1 Gene Research Articles

Single Nucleotide Polymorphisms of Cytokine Genes are Associated with Fibrosis of the Intrahepatic Bile Duct Wall in Human Clonorchiasis

This study examined the association of cytokine gene polymorphisms with intrahepatic bile duct wall fibrosis in human clonorchiasis. A total of 240 residents in Heilongjiang, China underwent ultrasonography, blood sampling, and stool examination. Single nucleotide polymorphism (SNP) sites for IFN-gamma (+874 T/A), IL-10 (-1,082 G/A, -819 C/T, -592 C/A), TNF-alpha (-308 G/A), and TGF-beta1 (codon 10 T/C, codon 25 G/C) genes were observed with the TaqMan allelic discrimination assay. No significant correlation was observed between individual cytokine gene polymorphisms and intrahepatic duct dilatation (IHDD). Among individuals with clonorchiasis of moderate intensity, the incidence of IHDD was high in those with IFN-gamma intermediate-producing genotype, +874AT (80.0%, P = 0.177), and in those with TNF-alpha low-producing genotype, -308GG (63.0%, P = 0.148). According to the combination of IFN-gamma and TNF-alpha genotypes, the risks for IHDD could be stratified into high (intermediate-producing IFN-gamma and low producing TNF-alpha), moderate, and low (low-producing IFN-gamma and high producing TNF-alpha) risk groups. The incidence of IHDD was significantly different among these groups (P = 0.022): 88.9% (odds ratio, OR = 24.0) in high, 56.5% (OR = 3.9) in moderate, and 25.0% (OR = 1) in low risk groups. SNP of IFN-gamma and TNF-alpha genes may contribute to the modulation of fibrosis in the intrahepatic bile duct wall in clonorchiasis patients.

Role of TGF-β1 (−509C>T) Promoter Polymorphism in Susceptibility to Cervical Cancer

Transforming growth factor-beta (TGF-beta) family members are multifunctional cytokines that play a key role in cellular growth, proliferation, and differentiation. The aim of study was to evaluate the association of TGF-beta1 -509 C>T gene polymorphism with risk of cervical cancer. The study was carried out in 150 histopathology confirmed patients with cervical cancer and 162 cervical-cytology negative females. Polymorphisms for TGF-beta1 -509C>T gene was genotyped by polymerase chain reaction and restriction enzyme digestion. Frequencies of individuals with -509TT genotype and T allele of TGF-beta1 gene polymorphisms did not differ significantly in patients with cervical cancer and controls (p = 0.328, OR = 1.37 and p = 0.605, OR = 1.09). Cervical cancer patients with -509TT had marginal low risk for stage I (p = 0.04, OR = 0.95, 95% CI = 0.91-0.99) but -509TT genotype of TGF-beta1 was associated with increased risk of stage II of cancer (p = 0.07, OR = 3.13, 95% CI = 0.87-11.14). In gene-environment interaction, carriers of TGF-beta1 -509TT genotype with tobacco usage were at higher risk of cervical cancer (OR = 3.67, 95% CI = 0.38-35.1). In conclusion, our data suggest that TGF-beta1 -509T allele confers marginal protection for early stage 1B but risk for stage II of cervical cancer.

Chronic Alcohol Feeding Stimulates the Formation of Mutagenic Etheno-Adducts in a Rodent model of NASH Via Induction of Cytochrome P450 2E1

Background and Aims: Chronic alcohol consumption may cause liver fibrosis and hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD). Synergistic effects of insulin resistance and alcohol triggering fibrogenesis and HCC are implicated. Formation of mutagenic etheno adducts binding to adenosin (EdA) generated via induced CYP2E1 has been suggested as a key mechanisms of hepatocarcinogenesis. Methods: Obese Zucker rats and lean littermates (4 groups) received Lieber-De Carli liquid diets containing either ethanol or carbohydrates for 3 months. Fibrosis and steatosis were quantified by Sirius Red and Oil Red O, respectively. EdA immunohistology was performed using a monoclonal antibody, and fibrosis-related gene and protein expression and hydroxyproline quantified. CYP2E1 and 4A2 were assayed at transcription and protein level. Results: Obese rats had more steatosis than lean animals but showed no aggravating impact of chronic alcohol intake. Histology and liver hydroxyproline showed similar extent of fibrosis in all groups. Procollagen alpha1(I), alpha smooth muscle actin, and TGFbeta-1 gene expression were not different. CYP2E1 protein was induced by 35% in both groups of obese rats, while corresponding mRNA levels were upregulated 3.5-fold in alcoholic lean rats. CYP4A2 was lower in obese rats, but upregulated 2-fold in those fed alcohol. In alcoholic obese and lean rats hepatocyte nuclei stained positive for EdA in 36% and 23%, respectively, but only 14% in obese rats without alcohol. EdA immunostaining was absent in lean non-alcoholic rats. EdA labelling correlated positively with CYP2E1 and 4-HNE immunostaining. Conclusions: Chronic alcohol feeding in obese, insulin-resistant rats exerts no effect on liver fibrosis formation, but potentiates the formation of mutagenic EdA possibly due to CYP2E1 induction. This observation may explain the increased risk of developing HCC in patients with NAFLD who chronically drink alcohol.

Cytokine gene polymorphisms and BALF cytokine levels in interstitial lung diseases

The aim of our study is to investigate correlations of T(H)1/T(H)2 cytokine gene polymorphisms and bronchoalveolar lavage fluid (BALF) cytokine values in interstitial lung diseases (ILD). In 16 sarcoidosis, 7 idiopathic pulmonary fibrosis (IPF) and 8 hypersensitivity pneumonitis (HP) patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis (p=0.0126). In the sarcoidosis group IL-4R alpha(+1902)AA and IL-10(-1082)G allele correlated with higher BALF ENA-78 levels (p=0.0258, p=0.0230). In the HP group the IL-6(-174)CG and IL-6(nt565)AG correlated with higher ENA-78 BALF levels (p=0.0253). In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values (p=0.046). BALF chemokine values did not differ between ILD subgroups, except for IL-8, which was higher in stage III sarcoidosis patients compared to stage I. Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in sarcoidosis, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.

Meniscal tissue explants response depends on level of dynamic compressive strain

Following partial meniscectomy, the remaining meniscus is exposed to an altered loading environment. In vitro 20% dynamic compressive strains on meniscal tissue explants has been shown to lead to an increase in release of glycosaminoglycans from the tissue and increased expression of interleukin-1alpha (IL-1alpha). The goal of this study was to determine if compressive loading which induces endogenously expressed IL-1 results in downstream changes in gene expression of anabolic and catabolic molecules in meniscal tissue, such as MMP expression. Relative changes in gene expression of MMP-1, MMP-3, MMP-9, MMP-13, A Disintegrin and Metalloproteinase with ThromboSpondin 4 (ADAMTS4), ADAMTS5, TNFalpha, TGFbeta, COX-2, Type I collagen (COL-1) and aggrecan and subsequent changes in the concentration of prostaglandin E(2) released by meniscal tissue in response to varying levels of dynamic compression (0%, 10%, and 20%) were measured. Porcine meniscal explants were dynamically compressed for 2h at 1Hz. 20% dynamic compressive strains upregulated MMP-1, MMP-3, MMP-13 and ADAMTS4 compared to no dynamic loading. Aggrecan, COX-2, and ADAMTS5 gene expression were upregulated under 10% strain compared to no dynamic loading while COL-1, TIMP-1, and TGFbeta gene expression were not dependent on the magnitude of loading. This data suggests that changes in mechanical loading of the knee joint meniscus from 10% to 20% dynamic strain can increase the catabolic activity of the meniscus.

Aryl hydrocarbon receptor polymorphism modulates DMBA‐induced inflammation and carcinogenesis in phenotypically selected mice

We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12-dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1beta, Tnf, Il6, Tgfbeta1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr(b1)), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor (Ahr(d)), to DMBA. The differential segregation of Ahr functional Ahr(d)versus Ahr(b1) alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines.

TGF-β1 gene polymorphisms and primary vesicoureteral reflux in childhood

The aim of this study was to assess the association between the transforming growth factor-beta1 (TGF-beta1) gene polymorphisms rs1800469 (commonly known as T-509C) and rs1982073 (commonly known as Leu (10)-->Pro) and primary vesicoureteral reflux (VUR) and renal scarring. Using a case-control approach, we examined 121 children with primary VUR and 169 controls. Genotyping of the TGF-beta1 gene polymorphisms was performed by restriction fragment length polymorphism (RFLP) analysis. The (99m)Tc-DMSA- or (99m)Tc-unitiol-single photon emission computed tomography method was used to evaluate renal scars in 84 of 121 VUR children. Statistical analysis revealed differences in rs1800469 genotype frequencies between VUR patients and controls (p = 0.0021). Our data demonstrate that individuals homozygous for the TT genotype are at risk of primary VUR [odds ratio (95% confidence interval) = 2.7 (1.46-5.08)]. Distribution of the rs1982073 polymorphism was similar in VUR children and controls. In terms of renal scarring, patients were stratified into non-scar and scar subgroups, and no differences in the genotype frequencies of either polymorphism was found. Previous reports have shown that the TT genotype of the rs1800469 polymorphism is a risk factor for renal scarring in primary VUR, and the results of our study suggest that this same polymorphism is associated with susceptibility to this congenital uropathy.

Gene Transfer and Living Release of Transforming Growth Factor-β3 for Cartilage Tissue Engineering Applications

Cartilage restoration continues to present a tremendous clinical challenge due to its nonvascular nature. Many studies have demonstrated that chondrogenesis of progenitor cells can be achieved in vitro by manual dose of growth factors; however, it remains a vital difficulty in feeding growth factors to implanted therapeutic cells in vivo. Herein, we constructed recombinant adenovirus encoding human transforming growth factor-beta3 (hTGF-beta3) and practiced it in rat bone marrow-derived mesenchymal stromal cells and articular chondrocytes for cartilage regeneration. Optimal viable transduction and transgenic hTGF-beta3 production were achieved; consequently, positive expression of cartilage marker-collagen type II was enabled in the infected progenitors. We thus conclude that recombinant adenovirus encoding TGF-beta3 gene has been successfully established and validated for cartilage tissue engineering applications.

Transcriptional regulation of theTGF-β1promoter by androgen receptor

TGF (transforming growth factor)-beta1 is a multifunctional cytokine that influences homoeostatic processes of various tissues. TGF-beta1 expression is inhibited by androgens in the prostate gland, whereas its expression is enhanced by androgens in highly metastatic prostate cancer cells. Here, we examined regulation of human TGF-beta1 promoter activity by androgen in prostate cancer cells. The full-length (-3363 to +110) promoter showed a high level of activity in response to androgen in PC3mm2 cells expressing AR (androgen receptor). Further deletion analysis revealed three distal and three proximal AREs (androgen-response elements) in the promoter. Gel-shift and footprint assays show that these AREs physically interact with the DNA-binding domain of AR. Chromatin immunoprecipitation assays revealed the androgen-dependent recruitment of AR to the ARE-containing regions of the TGF-beta1 gene. More importantly, a negative ARE was detected in the TGF-beta1 promoter. Both positive and negative AREs are functional in the androgen-regulated transcription of the TGF-beta1 promoter. These findings imply that androgen signalling may positively or negatively regulate TGF-beta1 expression in response to various signals or under different environmental conditions.

IL‐10 gene polymorphism, but not TGF‐β1 gene polymorphisms, is associated with food allergy in a Japanese population

The regulatory IL-10 and TGF-beta1 cytokine gene polymorphisms have been associated with allergic diseases in different populations, like Caucasian, Chinese and Indians. We investigated the association between the polymorphisms IL-10 A-1082G, C-819T, C-627A and TGF-beta1 T+869C, G+915C, C-509T and food allergy in Japanese children. One hundred and eleven children with food allergy and 115 atopic control children without food allergy were recruited. DNA samples from these subjects were genotyped by using PCR. The odds ratio of IL-10 -1082 AA genotype was 2.5 (95% CI, 1.0-6.4) for food allergy risk when compared with atopic control subjects (p = 0.03). There were no significative differences in the frequency of TGF-beta1 gene polymorphisms between both groups. Our results indicate that IL-10 A-1082G gene polymorphism is associated with food allergy susceptibility in atopic Japanese children.

The G/G genotype of transforming growth factor beta 1 (TGF‐β1) single nucleotide (+915G/C) polymorphism coincident with other host and environmental factors is associated with irreversible bronchoconstriction in asthmatics

Irreversible airflow obstruction may develop in some cases of asthma even in absence of known risk factors such as smoking and environmental insults and despite implementing apparently appropriate therapy. This implies that genetic factors may significantly contribute to determining the severity in the course of the disease. The published reports on genetic predisposition to irreversible bronchoconstriction in asthma, however, are relatively scarce, and disregard its potential association with transforming growth factor (TGF)-beta1 gene polymorphism despite established role that TGF-beta1 plays in airway remodelling. We tested TGF-beta1 single-nucleotide polymorphisms (SNPs) at position +869 of codon 10 (leucine or proline) and position +915 of codon 25 (arginine or proline) for association with irreversible bronchoconstriction in a case-control study involving 110 patients with asthma and 109 controls. Multivariate logistic regression analysis revealed that genotype G/G at codon 25 was significantly associated with irreversible bronchoconstriction in asthmatics (odds ratio = 4.44; 95% confidence interval: 1.00-19.61; P = 0.05), but only after adjustment for gender, disease duration and smoking index. The influence of SNPs at codon 10 on irreversible airway obstruction was not significant. Our results suggest that presence of SNP (+915G/G) at codon 25 in TGF-beta1 gene may predispose to the development of irreversible bronchoconstriction in asthmatic patients, but only when coincident with the male gender, habitual smoking and relevant duration of the disease.

Association between a TGFβ1 promoter polymorphism and the phenotype of aspirin-intolerant chronic urticaria in a Korean population

Chronic urticaria/angioedema is a common phenotype in patients with aspirin sensitivity; however, its genetic mechanism is not understood. Transforming growth factor (TGF)beta1 is a key regulatory cytokine involved in allergic inflammation. We examined the association of a TGFbeta1 genetic polymorphism with aspirin-intolerant chronic urticaria (AICU) and aspirin-tolerant chronic urticaria (ATCU) in a Korean population. A promoter polymorphism in the TGFbeta1 gene, TGFbeta1 -509C>T, was analysed in 112 AICU patients, 153 ATCU patients and 457 normal controls (NC), and the frequency was compared among the groups. Serum TGFbeta1 levels were measured by ELISA. The minor allele frequency of the -509C>T polymorphism was significantly higher in patients with AICU compared with the other two groups (P < 0.02 for AICU vs. NC; P < 0.05 for AICU vs. ATCU). Among the AICU patients, those with the T allele tended to have lower serum TGFbeta1 levels. These findings suggest that the -509C>T polymorphism in the TGFbeta1 promoter may contribute to the development of the AICU phenotype.

Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminoglycan chain synthesis during cartilage destruction and repair

Osteoarthritis and rheumatoid arthritis are characterized by loss of proteoglycans (PGs) and their glycosaminoglycan (GAG) chains that are essential for cartilage function. Here, we investigated the role of glycosyltransferases (GTs) responsible for PG-GAG chain assembly during joint cartilage destruction and repair processes. At various times after antigen-induced arthritis (AIA) and papain-induced cartilage repair in rats, PG synthesis and deposition, expression of GTs, and GAG chain composition were analyzed. Our data showed that expression of the GT xylosyltransferase I (XT-I) gene initiating PG-GAG chain synthesis was significantly reduced in AIA rat cartilage and was associated with a decrease in PG synthesis. Interestingly, interleukin-1beta, the main proinflammatory cytokine incriminated in joint diseases, down-regulated the XT-I gene expression with a concomitant decrease in PG synthesis in rat cartilage explants ex vivo. However, cartilage from papain-injected rat knees showed up-regulation of XT-I gene expression and increased PG synthesis at early stages of cartilage repair, a process associated with up-regulation of TGF-beta1 gene expression and mediated by p38 mitogen-activated protein kinase activation. Consistently, silencing of XT-I expression by intraarticular injection of XT-I shRNA in rat knees prevented cartilage repair by decreasing PG synthesis and content. These findings show that GTs play a key role in the loss of PG-GAGs in joint diseases and identify novel targets for stimulating cartilage repair.

Ventral Mesencephalon Astrocytes Are More Efficient Than Those of Other Regions in Inducing Dopaminergic Neurons Through Higher Expression Level of TGF-β3

Being supportive cells for neurons in the central nervous system, astrocytes have recently found to be associated with neurogenesis. Ventral mesencephalon (VM) astrocytes were also detected being instructive for VM dopaminergic (DA) neurogenesis, but the underling mechanisms are still unclear. This research is to figure out whether VM astrocytes are more efficient than those from other brain regions in inducing VM DA neurons from their precursors and whether transforming growth factor-betas (TGF-betas) are the underlying molecules. We found that, compared with astrocytes preparations from striatum and hippocampus, VM astrocytes preparations displayed markedly higher efficacy in inducing DA neurogenesis. Besides, they also expressed higher level of TGF-beta3 than those of two other regions. When TGF-beta3 gene expression in astrocytes preparations was inhibited by its antisense oligonucleotide, the induction of DA neurons decreased to a similar level among these three astrocytes preparations. Thus, our experiment indicates that VM astrocytes preparations which contained highly purified astrocytes are more efficient in inducing DA neurogenesis than those from other regions. Furthermore, it also suggests that the regional differences are regulated by different expression levels of TGF-beta3 in those astrocytes preparations from different derivations.

DNA profiling by array comparative genomic hybridization (CGH) of peripheral blood mononuclear cells (PBMC) and tumor tissue cell in non-small cell lung cancer (NSCLC)

Lung tumor cell DNA copy number alteration (CNA) was expected to display specific patterns such as a large-scale amplification or deletion of chromosomal arms, as previously published data have reported. Peripheral blood mononuclear cell (PBMC) CNA however, was expected to show normal variations in cancer patients as well as healthy individuals, and has thus been used as normal control DNA samples in various published studies. We performed array CGH to measure and compare genetic changes in terms of the CNA of PBMC samples as well as DNA isolated from tumor tissue samples, obtained from 24 non-small cell lung cancer patients. Contradictory to expectations, our studies showed that the PBMC CNA also showed chromosomal variant regions. The list included well-known tumor-associated NTRK1, FGF8, TP53, and TGFbeta1 genes and potentially novel oncogenes such as THPO (3q27.1), JMJD1B, and EGR1 (5q31.2), which was investigated in this study. The results of this study highlighted the connection between PBMC and tumor cell genomic DNA in lung cancer patients. However, the application of these studies to cancer prognosis may pose a challenge due to the large amount of information contained in genetic predisposition and family history that has to be processed for useful downstream clinical applications.

Lack of Association between Cytokine Gene Polymorphisms and Silicosis and Pulmonary Tuberculosis in Chinese Iron Miners

Silicosis is a fibrotic lung disease produced by the inhalation and deposition of silica dust. The association between silicosis and pulmonary tuberculosis (PTB) has been well established. Cytokines participate in the development and progression of silicosis and PTB. Functional polymorphisms in cytokine genes have been identified that alter cytokine production. The aims of the current investigation were to determine whether functional polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) gene at position -308; in the transforming growth factor-beta 1 (TGF-beta1) gene at positions -509, +869 (codon 10), and +915 (codon 25); in the interleukin-10 (IL-10) gene at position -1,082, -819 and -592; and in the intron 1 of the interferon-gamma (IFN-gamma) gene at position +874 are associated with silicosis and PTB. We conducted a case-control study with 183 silicosis patients and 111 silica-exposed miners, and a 1:2 matched case-control study of 61 PTB cases and 122 PTB-free miners. Genotype analysis was performed on genomic DNA, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. There was complete linkage disequilibrium (LD) between the -819C and -592C alleles of the IL-10 gene. The genotype frequencies were similar between cases and control subjects for all investigated cytokine polymorphisms (p>0.05). We did not find an association between the different genotypes and severity of silicosis. We assume that these genetic variants do not play a dominant role in silicosis and PTB in our Chinese population.

C-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways that facilitate collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of JNK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK1-/- mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK1-/- mice accumulated less subepithelial collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-beta1 content in the bronchoalveolar lavage was diminished in JNK1-/- mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-beta1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting collagen deposition in multiple models of fibrosis.

Single Nucleotide Polymorphism T(861-20)C in TGFbeta1 Gene Affects its Expression in Peripheral Blood Mononuclear Cells in Russian Postmenopausal Women

Single Nucleotide Polymorphism T(861-20)C in TGFbeta1 Gene Affects its Expression in Peripheral Blood Mononuclear Cells in Russian Postmenopausal Women

Expression and actions of transforming growth factors during human follicular development

To correlate the temporal expression of transforming growth factor-alpha (TGF-alpha) and TGF-beta genes in granulosa cells (GC) and thecal cells from human follicles at various developmental stages and to determine their trophic effects on GCs. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of extracted RNA from follicular GCs and theca cells. Academic endocrinology laboratory. Premenopausal women undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy for nonovarian reasons. None. Confirmation by the RT-PCR product for TGF-alpha and TGF-beta gene expression in GC and theca cells from human follicles at various developmental stages and (3)H-thymidine uptake in vitro to assess growth effects on GCs. The RT-PCR product indicating the presence of TGF-alpha messenger RNA (mRNA) was found consistently in theca from healthy antral follicles. In theca from large follicles (>1.0 cm) the TGF-alpha PCR product was of reduced intensity. The TGF-alpha was absent or undetectable in granulosa cells from all follicle sizes. The PCR product for TGF-beta was generated by all GC and thecal cell RNAs from all follicle sizes examined. The TGF-alpha promoted and TGF-beta inhibited human GC growth. The presence of TGF-alpha gene expression in thecal cells coincides with periods of follicular growth. The expression of TGF-beta occurs in both cell types throughout antral follicle development. The TGF-alpha and TGF-beta have opposing trophic effects on GCs.

Association between transforming growth factor-beta 1 polymorphism and virologic characteristics of chronic hepatitis C

The production of transforming growth factor beta 1 (TGF-beta1) has been reported as being significantly associated with the gene polymorphism in the leader sequence at positions +29. The current study aimed to evaluate the associations between the polymorphism and the clinical characteristics of chronic hepatitis C (CHC). A total of 422 (252 men; mean age: 49.7 +/- 11.2 years) Taiwanese CHC patients with liver biopsies were enrolled. The TGF-beta1 gene polymorphism at position +29 (T or C), hepatitis C virus (HCV) RNA genotypes, and serum HCV RNA levels of these patients were determined. Of the 422 patients, the frequency of the T allele was 45.4%. Based on univariate analyses, a significantly lesser proportion of patients with allele T had high viral loads than those who were without allele T (P = 0.026). The lesser HCV RNA levels and HCV genotype 1b infection were significantly associated with the inheritance of the T allele in female patients based on univariate (P = 0.012 and 0.007, respectively) and multivariate regression (odds ratio/95% confidence interval: 0.434/0.219-0.859 and 0.468/0.237-0.927, respectively) analyses. In male patients with or without inheritance of the T allele, the clinical characteristics were similar. In conclusion, the association between TGF-beta1 polymorphism and virologic characteristics of chronic HCV infection implicated a significant role of host genetic factors on the clinical features of CHC. Female patients who carry T allele at position +29 were predisposed to be associated with HCV genotype non-1b infection and lesser HCV viral load, which revealed the gender effect.