Serum TGF-beta1 Levels Research Articles

Oral Calcitriol for the Treatment of Persistent Proteinuria in Immunoglobulin A Nephropathy: An Uncontrolled Trial

Laboratory research and previous retrospective study suggest that vitamin D and its analogues have profound effects on immune system function and glomerular mesangial cell proliferation. We conducted an open-label study to evaluate the antiproteinuric effect of calcitriol on proteinuria in patients with immunoglobulin A (IgA) nephropathy. Open-label prospective uncontrolled trial. 10 patients (3 men) with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy in a tertiary referral center. Calcitriol, 0.5 microg, twice weekly for 12 weeks. Changes in proteinuria, renal function, serum transforming growth factor beta (TGF-beta) and angiotensin II levels. After calcitriol treatment, there was a significant overall decrease in proteinuria with time by using a general linear model with repeated measures (P = 0.03). There was a progressive decrease in urine protein-creatinine ratio from 1.98 +/- 0.74 to 1.48 +/- 0.81 g/g (P = 0.007) during the first 6 weeks that persisted throughout the study period. No significant change in blood pressure or renal function was noted. There was a simultaneous decrease in serum TGF-beta level, and percentage of decrease in serum TGF-beta level significantly correlated with percentage of change in proteinuria (Spearman r = 0.643; P = 0.02). Serum angiotensin II level did not change throughout the study. One patient experienced transient hypercalcemia that normalized after a dosage decrease. No other major adverse effect was reported. This small study is uncontrolled and does not examine the long-term effect of calcitriol therapy. Twice-weekly oral calcitriol has a modest antiproteinuric effect in patients with IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Additional studies are needed to confirm the renal protecting effect of calcitriol in patients with chronic proteinuric kidney diseases.

Bolus infusion of human urinary trypsin inhibitor improves intractable interstitial pneumonia in patients with connective tissue diseases

Interstitial pneumonia (IP) associated with CTDs often progresses despite conventional immunosuppressive treatment. We investigated the efficacy of human urinary trypsin (UT) inhibitor (ulinastatin) on refractory IP. Five patients with IP received UT inhibitor (3 x 10(5) U) infusion into the internal jugular vein, three times in a single day. The response to this therapy was assessed clinically and by chest CT, PaO(2) and serum KL-6. The kinetics of UT inhibitor was determined in arterial blood. We measured serum levels of monocyte chemotactic protein-1 and TGF-beta1, which are thought to be involved in the pathogenesis of IP. Serum concentrations of UT inhibitor increased immediately to >150 U/ml after infusion of 3 x 10(5) U of UT inhibitor. The treatment resulted in clinical and radiological improvements in four patients, and allowed reduction of oxygen therapy following improvement of hypoxaemia within 1 month. UT inhibitor decreased serum levels of KL-6 in all patients and had no adverse effects. MCP-1 and TGF-beta1 concentrations were higher in the patients than in normal subjects, and infusion of 3 x 10(5) U of UT reduced the concentrations within 3 h of infusion. UT inhibitor bolus infusion therapy is a potentially useful therapeutic strategy for intractable IP based on the different mechanism of action relative to conventional immunosuppressive therapy and lack of serious treatment-related adverse effects.

Bifidobacteriummicrobiota and parameters of immune function in elderly subjects

Faecal and serum samples were collected over a period of 6 months from 55 institutionalized elderly subjects, who were enrolled in a double-blind placebo-controlled study. Participants were randomized in one of the three treatment groups: intervention (two probiotic Bifidobacterium longum strains: 2C and 46), placebo and commercial control (Bifidobacterium lactis Bb-12). The faecal Bifidobacterium microbiota was characterized by genus and species-specific PCR. Serum levels of the cytokines IL-10, tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 were determined by enzyme-linked immunosorbent assay. Each participant harboured on average approximately three different bifidobacterial species. The most frequently detected species were B. longum, Bifidobacterium adolescentis and Bifidobacterium bifidum. Depending on the treatment, the intervention resulted in specific changes in the levels of certain Bifidobacterium species, and positive correlations were found between the different species. Negative correlations were observed between the levels of Bifidobacterium species and the pro-inflammatory cytokine TNF-alpha and the regulatory cytokine IL-10. The presence of faecal B. longum and Bifidobacterium animalis correlated with reduced serum IL-10. The anti-inflammatory TGF-beta1 levels were increased over time in all three groups, and the presence of Bifidobacterium breve correlated with higher serum TGF-beta1 levels. This indicates that modulation of the faecal Bifidobacterium microbiota may provide a means of influencing inflammatory responses.

Hashimoto's Thyroiditis, but not Treatment of Hypothyroidism, Is Associated with Altered TGF-β1 Levels

Although the role of cytokines in the development of Hashimoto's thyroiditis has already been established, its pathogenesis has not yet been clearly elucidated. The aim of our study was to investigate serum transforming growth factor-beta1 (TGF-beta1) levels in patients with Hashimoto's thyroiditis as well as the effect of achieving euthyroidism by levothyroxine replacement on TGF-beta1 levels. Twenty nine female, newly diagnosed hypothyroid Hashimoto's thyroiditis patients (16 overt, 13 subclinical hypothyroid) and 25 age- and sex-matched healthy controls were enrolled in the study. Serum TGF-beta1 levels were lower in the Hashimoto's thyroiditis group when compared with control cases. Although significant differences were noted in lipid levels and in anthropometric measurements following levothyroxine replacement, serum TGF-beta1 levels remained unchanged. Our data suggest that altered TGF-beta1 levels are associated with the presence of Hashimoto's thyroiditis, not with the treatment of thyroid dysfunction. Autoimmunity may have been triggered as a result of decreased immunosuppressive effect induced by depressed TGF-beta1 levels in patients with Hashimoto's thyroiditis.

Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria.

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNgamma, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4+ CD25+ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFbeta, TGFbetaRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFbeta and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25+ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.

Elevated serum level and gene polymorphisms of TGF‐β1 in gastric cancer

Transforming growth factor (TGF)-beta1, as a candidate tumor marker, is currently of interest. In this study, serum TGF-beta1 levels in gastric cancer (GC) patients and healthy volunteers were measured using enzyme-linked immunosorbent assay (ELISA). In addition, single nucleotide polymorphisms (SNPs) of the TGF-beta1 gene at codon 10 and codon 25 were identified by means of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and sequence analysis. Our results indicated that serum concentrations of TGF-beta1 in GC patients were significantly higher than those in the control, and positively correlated with tumor mass, invasion, metastasis, and clinical stage. The serum TGF-beta1 levels of patients recovering from radical resection were markedly lower than those before surgery. Meanwhile, no deoxyribonucleic acid (DNA) sequence variation at codon 25 of the TGF-beta1 gene was found and a TGF-beta1 gene polymorphism at codon 10 did not show obvious correlations with either TGF-beta1 expression or clinicopathological parameters of GC. Our evidence suggested that serum concentration of TGF-beta1 might be a novel tumor marker for GC and the polymorphisms of TGF-beta1 gene did not play a role as a determinant of serum TGF-beta1 concentration or as a genetic risk factor in the gastric carcinogenesis and progression.

Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans

To clarify whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of chronic pancreatitis (CP). This study aimed at clarifying whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of CP. Serum monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta-1 (TGF-beta1), and soluble type fractalkine (s-fractalkine) concentrations were examined in patients with CP (n = 109) and healthy controls (n = 116). Severity of disease was classified in patients with CP by a staging system. Relationships between stage-specific various clinical factors and serum MCP-1, TGF-beta1, and s-fractalkine levels were investigated. Furthermore, 57 patients with non-alcoholic CP were similarly evaluated in order to exclude influence of alcohol intake. Patients with CP showed significant higher levels of serum TGF-beta1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-beta1 in the severe stage and s-fractalkine in the mild and the severe stage of CP significantly increased compared to those of controls. However, it was observed that both TGF-beta1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-beta1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed significant increase in the early stage of CP. It is suggested that the measurement of serum F-fractalkine is useful to diagnose early-stage CP. Moreover, the combined determination of both, s-fractalkine and TGF-beta1, in human sera may be helpful in evaluating the severity status of CP.

Effectiveness of etanercept in bleomycin-induced experimental scleroderma

To evaluate the effects of etanercept and thalidomide in the mouse model of bleomycin-induced scleroderma (BLM-IS). This study involved four groups (n = 8 mice in each group). Dermal sclerosis was induced by repeated subcutaneous injections of BLM (10 microg) for 4 weeks in BALB/c mice. Control group received only phosphate-buffered saline. The second group received only BLM; the third and fourth groups were also given an intraperitoneal injection of 100 microg etanercept or 150 mg/kg thalidomide, respectively. BLM increased serum TGF-beta1, tissue hydroxyproline levels and expression of alpha-smooth muscle actin (alpha-SMA), and dermal fibrosis was histopathologically prominent. Although thalidomide had no significant effect, etanercept caused decreases in levels of serum TGF-beta1, tissue hydroxyproline and number of alpha-SMA-positive cells. Inhibition of TNF-alpha with etanercept in BLM-IS was resulted in a significant reduction of the dermal sclerosis, collagen accumulation and the number of infiltrating myofibroblastic cells. TNF-alpha may play a key role in the progression of BLM-IS and TNF-alpha antagonists may be useful in the management of scleroderma.

Cytokine Levels of TGF-β, IL-10, and sTNFαRII in Type C Chronic Liver Disease

Cytokines play a key role in regulation of immunity and inflammation. The aim of the study was to detect serum levels of TGF-beta, IL-10, and sTNFalphaRII in patients with type C chronic liver disease (CLD) and to correlate these with biochemical and histopathological parameters used to assess the severity of the disease. Blood samples were aseptically collected from 90 CLD patients. Cytokine levels were also followed up in 39 chronic hepatitis cases. Levels of the cytokines in 90 CLD patients were significantly higher than in controls. In the follow up patients, 12 were non-responders and the serum levels of cytokines were still elevated after therapy whereas in 27 responders cytokine levels were significantly reduced after therapy and correlated well with biochemical and histopathological parameters. It is inferred that cytokine levels reflect the level of inflammation in chronic hepatitis C virus (HCV) infection and can be used as indirect markers to assess the severity of liver disease.

Serum levels and genetic variation of TGF-β1 are not associated with Alzheimer’s disease

As transforming growth factor-beta1 (TGF-beta1) determines important neurotrophic and neuroprotective actions, we postulated serum TGF-beta1 levels could be low in Alzheimer's disease (AD), and TGF-beta1 genetic variation could be associated with AD risk through modulating serum TGF-beta1 levels. TGF-beta1 (-800) (rs 1800468), (-509) (rs 1800469) and (+869) (rs 1982073) polymorphisms were genotyped in 412 AD patients and 406 controls. We measured serum TGF-beta1 levels (by ELISA) in 63 AD patients and compared them with 77 age- and gender-matched non-demented controls. Serum TGF-beta1 levels were not different in AD patients than in controls. Distribution of the allele and genotype frequencies of TGF-beta1 polymorphisms did not differ between AD patients and controls. There was no significant correlation between serum TGF-beta1 levels and TGF-beta1 polymorphisms. Serum TGF-beta1 concentration is not a potential biomarker for AD, and TGF-beta1 genetic variants (-800, -509, and +869) are not risk factors for AD.

TGFB1 promoter polymorphism C-509T and pathophysiology of asthma

TGF-beta1 can modulate airway inflammation and exaggerate airway remodeling. A polymorphism of a promoter region of TGFB1, C-509T, might be associated with the development of asthma, but its pathophysiologic relevance remains poorly understood. We investigated relations of the C-509T polymorphism to airflow obstruction, sputum eosinophilia, and airway wall thickening, as assessed by means of computed tomography, in 85 patients with stable asthma. The CC, CT, and TT genotypes were examined by means of PCR and restriction enzyme fragment length polymorphism. At a selected bronchus, 3 indices of airway wall thickness were measured with an automatic method. The CC, CT, and TT genotypes were found in 22, 46, and 17 patients, respectively. Serum TGF-beta1 levels were significantly associated with the polymorphism and were increased in the CT/TT genotypes. FEV(1) and sputum eosinophil percentages were also significantly associated with the polymorphism and were both decreased in the CT/TT genotypes. The polymorphism was unrelated to airway wall thickness. In addition to increased serum TGF-beta1 levels, the T allele of the C-509T polymorphism is related to increased airflow obstruction but attenuated eosinophilic inflammation. The former relation is not attributed to thickening of the central airway walls. The latter relation might reflect the anti-inflammatory effect of TGF-beta1. The C-509T polymorphism has a complex role in asthma pathophysiology, presumably because of the diverse functions of TGF-beta1 and its various interactions with cells and humoral factors in vivo.

FDG uptake by the bone marrow in NSCLC patients is related to TGF-β but not to VEGF or G-CSF serum levels

Non small cell lung carcinomas (NSCLC) are known to secrete various cytokines such as VEGF (vascular endothelial growth factor), G-CSF (granulocyte-colony stimulating factor) and TGF-beta (transforming growth factor-beta) that may stimulate bone marrow activity. This study reports on the relationship between serum levels of VEGF, G-CSF, TGF-beta and FDG uptake by the bone marrow in NSCLC patients. Thirty-three patients suffering from newly diagnosed NSCLC who were successively referred to undergo an FDG PET scan as a part of their routine staging procedure and that did not suffer from bone metastases were included in the study. FDG bone marrow activity was determined in all patients and related to pre-treatment VEGF, G-CSF and TGF-beta serum levels. Mean standardized uptake values (SUV mean) of the bone marrow ranged from 0.1 to 2.1 (mean 1.1). G-CSF, VEGF and TGF-beta serum levels ranged from 13.5 to 110 pg/ml (mean 41.4 pg/ml), from 95 to 3,221 pg/ml (mean 1,111 pg/ml) and from 269 to 615 pg/ml (mean 387 pg/ml), respectively. SUV mean values of the bone marrow significantly correlated with TGF-beta serum measurements (r = 0.621, p < 0.0001), but not with VEGF and G-CSF measurements. FDG uptake by bone marrow in newly diagnosed NSCLC patients correlates with serum levels of TGF-beta, but not with VEGF or G-CSF levels.

Systemic inflammation in chronic obstructive pulmonary disease and asthma: Similarities and differences

While recent studies have shown that patients with COPD and patients with asthma exhibit evidence of airway and systemic inflammation, markers of systemic inflammation have not been compared between the two diseases. To evaluate circulating inflammatory markers, blood was sampled from 111 patients with COPD, 75 control subjects and 46 asthmatic patients (some of whom were smokers). Measurements of WCC, serum levels of fibrinogen, high-sensitivity (hs)-CRP, IL-8, IL-6, tumour necrosis factor-alpha (TNF-alpha), transforming growth factor (TGF)-beta1, tissue inhibitors of metalloproteinase (TIMP)-1, neutrophil elastase and alpha1-antitrypsin (alpha1-AT) were performed. Serum TNF-alpha, IL-6 and TIMP-1 concentrations were significantly higher in patients with stable COPD and patients with asthma than in control patients. Serum alpha1-AT levels were significantly higher in COPD patients than in asthmatic patients and control subjects, and serum TGF-beta1 levels were higher in asthma patients than in COPD patients. Smoking status had no effect on markers in COPD and asthmatic patients. Although COPD and asthma share common markers of systemic inflammation, serum levels of TGF-beta1 and alpha1-AT may reflect differences between the diseases.

Abstract 2959: TGF-beta Is A Promising Biomarker For Monitoring The Aortic Root Dilatation And Losartan Therapy In Marfan Syndrome

Objectives: Aortic root dilatation is the main cause of morbidity and mortality in Marfan syndrome (MFS), a disorder caused by mutations in the gene encoding fibrillin-1 and consequent dysregulation of TGF-beta signaling. The aim of this study was to discover a serological biomarker for the aortic root dilatation in a mouse model of MFS, that was also responsive to losartan therapy. Methods: Serum samples from mice heterozygous for a fibrillin-1 missense mutation (C1039G/+) and wild-type mice treated with losartan or placebo were obtained at 10 weeks, 6 months and 10 months of age. Total (acid activated) TGF-beta 1 serum concentrations were measured by ELISA. Echo measurements of the aortic root were obtained from a parasternal long axis view at 10 months of age. Results: Mean TGF-beta serum concentrations were higher in C1039G/+ mice compared to wild-type mice (p=0.01; 80.0 ng/ml (n=5) vs. 58.3 ng/ml (n=4) at 10 weeks, 117.4 ng/ml (n=11) vs. 87.0 ng/ml (n=6) at 6 months, 137.5 ng/ml (n=3) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Losartan-treated C1039G/+ mice had significantly lower mean TGF-beta serum levels compared to C1039G/+ mice with placebo (p=0.007; 92.9 ng/ml (n=5) vs. 117.4 ng/ml (n=11) at 6 months, 101.2 ng/ml (n=13) vs. 137.5 ng/ml (n=3) at 10 months, respectively). Mean TGF-beta serum concentrations in losartan-treated C1039G/+ mice and wild-type mice with placebo were not significant different (p=0.3; 92.9 ng/ml (n=5) vs. 87.0 ng/ml (n=6) at 6 months, 101.2 ng/ml (n=13) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Echo analyses revealed significantly smaller mean aortic root diameters in 10 months old wild-type and losartan-treated C1039G/+ mice compared to age-matched C1039G/+ mice with placebo (p=0.001; 1.94 mm (n=2) and 2.06 mm (n=13) vs. 2.4 mm (n=3), respectively). Conclusions: TGF-beta serum levels are higher in C1039G/+ mice compared to wild-type mice. Losartan treatment of C1039G/+ mice reduces TGF-beta serum concentrations and aortic root diameters towards wild-type levels. Serum TGF-beta is a promising biomarker for prognostication and monitoring the therapeutic response to losartan therapy in Marfan syndrome.

Influence of the selective oestrogen receptor modulator (raloxifene hydrochloride) on IL-6, TNF-alpha, TGF-beta1 and bone turnover markers in the treatment of postmenopausal osteoporosis.

Osteoporosis that is encountered frequently in postmenopausal women, may cause an increased incidence of vertebral and iliac fractures that are associated with excess morbidity. Raloxifene hydrochloride, a selective oestrogen receptor modulator, has been shown to increase bone mineral density and decrease biochemical markers of bone turnover in postmenopausal women, without stimulatory effects on breast or uterus. Levels of proinflammatory cytokines, including IL-6, and TNF-alpha and TGF-beta1 which are important cytokines involved in remodeling, have been evaluated previously in in vitro studies of osteoporosis. However, there seems to be a paucity of in vivo research concerned with changes in these cytokines in osteoporosis. In this study, we evaluated the effects of raloxifene (Evista); Lilly Pharmaceutical Co. USA, 60 mg/day) on biochemical bone turnover markers, serum parathyroid hormone, and 25-OH vitamin D, as well as the serum levels of IL-6, TNF-alpha and TGF-beta1, in 22 postmenopausal, osteoporotic women before and after 12 weeks of raloxifene treatment. Well-matched, postmenopausal, non-osteoporotic control subjects were also enrolled in the study. Serum levels of all the parameters were measured in postmenopausal, osteoporotic women at baseline and end of the study. It was found that serum osteocalcin and parathyroid hormone, and urine deoxypyridinoline levels decreased to normal levels with treatment. Serum 25-OH vitamin D levels after treatment in the patient group were higher than those in the control group. Serum IL-6, TNF-alpha and TGF-beta1 levels did not change significantly with treatment. However, serum levels of IL-6 and TGF-beta1 in the patient group after treatment, decreased to levels lower than those found in the control group. Serum TNF-alpha levels in the patient group before and after treatment, were lower than those in the control group. Raloxifene treatment reduces bone turnover biochemical markers, parathyroid hormone and induces 25-OH vitamin D in postmenopausal women. Moreover, it also affects some serum cytokine levels in the postmenopausal period.

Transforming growth factor β‐1 as a predictor of fibrosis in tuberculous pleurisy

To clarify the influence of transforming growth factor beta-1 (TGF-beta(1)) in the development of pleural thickening in tuberculosis (TB), the levels of TGF-beta(1) in pleural fluid and in serum of patients with pleural TB and transudative effusions were determined. TGF-beta(1) was quantified in 58 pleural fluid and serum samples of patients with TB (n = 50) or transudative effusions (n = 8). Pleural thickening evaluated by high-resolution CT was scored as 0 (<3 mm); 1 (>or=3 and <10 mm) or 2 (>or=10 mm). The highest pleural fluid TGF-beta(1) levels before treatment for TB were observed in patients with a pleural thickness score of 2. Of the 14 patients with score 1, five regressed to 0, five progressed to 2, and four maintained 1. All 17 patients with score 2 maintained this evaluation. Patients who presented score 1 and progressed to 2 had higher TGF-beta(1) levels than those who maintained the same score or regressed (score 1 or 0). Patients with score 2 (before or after treatment) had higher TGF-beta(1) levels than those with score 0 or 1. Pleural fluid and serum TGF-beta(1) levels were higher in patients with TB, with a correlation between pleural fluid TGF-beta(1) levels before treatment and the degree of pleural thickening. This finding suggests that TGF-beta(1) might be considered as a predictor of pleural thickening in pleural tuberculosis.

TGFB1 and TGFBR2 functional polymorphisms and risk of esophageal squamous cell carcinoma: a case–control analysis in a Chinese population

Transforming growth factor beta1 (TGF-beta1) and its receptor II (TGF-betaRII) are two key components of TGF-beta signaling and play an important role in carcinogenesis. Several functional polymorphisms were identified in TGFB1 and TGFBR2 and associated with elevated serum or plasma level of TGF-beta1 and enhanced transcription activity of TGFBR2. This population-based case-control study was to evaluate the contribution of functional polymorphisms in TGFB1 C-509T, Leu10Pro and TGFBR2 G-875A to the risk of esophageal squamous cell carcinoma (ESCC). Genotyping was performed using the primer-introduced restriction analysis-PCR assay in 255 ESCC cases and 704 cancer-free controls in a Chinese population. The variant genotypes (-509CT/TT) of TGFB1 C-509T were associated with a 63% significantly decreased risk of ESCC (adjusted OR = 0.37, 95% CI = 0.27-0.50) compared with -509CC wild-type homozygote. In addition, a moderately decreased risk of ESCC was related to -875GA (adjusted OR = 0.70, 95% CI = 0.49-0.99) but not -875AA genotype (adjusted OR = 1.09, 95% CI = 0.51-2.35) in TGFBR2, compared with -875GG common genotype. Furthermore, subjects carrying variant genotypes either or both of TGFB1 C-509T and TGFBR2 G-875A had a significantly reduced risk of ESCC (adjusted OR = 0.37, 95% CI = 0.26-0.53 for either one variant genotype and adjusted OR = 0.30, 95% CI = 0.19-0.48 for both variant genotypes) in a dose-response manner (chi (trend) (2) = 33.87, P < 0.001) compared with subjects with both wild-type genotypes. These results are consistent with our previous findings in gastric cancer and support the hypothesis that genetic variants in TGFB1 and TGFBR2 may modulate the risk of ESCC.

Osteopontin expression in oral lichen planus

To explore circulation levels of osteopontin (OPN), tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 from patients with oral lichen planus (OLP) for clinical application. A group of 26 subjects with OLP were compared with 26 sex- and age-matched control (NC) subjects. Local lesion tissue was examined for OPN by immunohistochemical analysis. And, serum OPN, proinflammatory TNF-alpha and TGF-beta1 levels were measured by enzyme-linked immunoabsorbent assay. The serum concentrations of OPN and TNF-alpha were significantly higher in OLP patients than the NC group (P < 0.05). Although serum concentrations of TGF-beta1 increased slightly, they were not statistically significant. Erosive-form OLP exhibited significantly elevated TGF-beta1 serum levels, compared with reticular-form OLP. The above results suggest that the production of OPN is associated with the inflammatory process of OLP development, and may serve as a potential disease marker of OLP.

Effects of Dexamethasone on the Expression of Transforming Growth Factor‐β in the Mouse Model of Allergic Rhinitis

This study aimed to evaluate the effect of dexamethasone on the expression of transforming growth factor (TGF)-beta in the mouse model of allergic rhinitis. Female BALB/c mice were randomly assigned to four groups, including two control groups and two treatment groups. General sensitization and local challenge were performed with ovalbumin (OVA). In the treatment groups, dexamethasone was injected intraperitoneally 3 hours before general sensitization or local challenge. Symptom score, eosinophil infiltration, and immunostaining for TGF-beta1 and CD4 in nasal mucosa, and TGF-beta1 and OVA-specific immunoglobulin E (IgE) in sera were analyzed. Dexamethasone administration before general sensitization reduced the symptom score, OVA-specific IgE, and eosinophil infiltration and increased the serum level of TGF-beta1 significantly. Dexamethasone administration before local challenge reduced only the eosinophil infiltration significantly. Immunoreactivity of TGF-beta1 and CD4 was lower in both treatment groups. These results suggest that dexamethasone may play an important role in the regulation of allergic reactions by at least two mechanisms; one by suppressing allergic sensitization through decrease of CD4+ T cells and increase of TGF-beta, and the other by suppressing late allergic reactions through the inhibition of proliferation and chemotaxis of inflammatory cells such as eosinophils.

Profibrogenic transforming growth factor-β/activin receptor–like kinase 5 signaling via connective tissue growth factor expression in hepatocytes

Connective tissue growth factor (CTGF) is important for transforming growth factor-beta (TGF-beta)-induced liver fibrogenesis. Hepatic stellate cells have been recognized as its major cellular source in the liver. Here we demonstrate the induction of CTGF expression in hepatocytes of damaged livers and identify a molecular mechanism responsible for it. CTGF expression was found by immunohistochemistry in bile duct epithelial cells, hepatic stellate cells, and hepatocytes in fibrotic liver tissue from patients with chronic hepatitis B infection. Similarly, CTGF expression was induced in hepatocytes of carbon tetrachloride-treated mice. CTGF expression and secretion were detected spontaneously in a medium of hepatocytes after 3 days of culture, which was enhanced by stimulation with TGF-beta. TGF-beta-induced CTGF expression was mediated through the activin receptor-like kinase 5 (ALK5)/Smad3 pathway, whereas activin receptor-like kinase 1 activation antagonized this effect. CTGF expression in the liver tissue of TGF-beta transgenic mice correlated with serum TGF-beta levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-beta-dependent and intrinsic CTGF expression, indicating that TGF-beta signaling was required. In line with these data, hepatocyte-specific transgenic Smad7 reduced CTGF expression in carbon tetrachloride-treated animals, whereas in Smad7 knockout mice, it was enhanced. Furthermore, an interferon gamma treatment of patients with chronic hepatitis B virus infection induced Smad7 expression in hepatocytes, leading to decreased CTGF expression and fibrogenesis. Our data provide evidence for the profibrogenic activity of TGF-beta directed to hepatocytes and mediated via the up-regulation of CTGF. We identify ALK5-dependent Smad3 signaling as the responsible pathway inducing CTGF expression, which can be hindered by an activated activin receptor-like kinase 1 pathway and completely inhibited by TGF-beta antagonist Smad7.