Transforming growth factor—beta 1 (TGF-β1) and TGF-β1 receptors in normal,cirrhotic, and neoplastic human livers

Transforming growth factor-Beta 1 (TGF-β1) is an important mediator of control of liver cell proliferation and replication. The aim of the current study was to compare TGF-β1 gene expression, protein synthesis, and cell membrane receptors in normal liver, cirrhotic nodules, and neoplastic human livers. Five surgical resections for metastasis in an otherwise normal liver and 25 resections for hepatocellular carcinoma with cirrhosis were included in this study. Messenger RNA (mRNA) and TGF-β1 protein were detected on serial tissue sections of normal, cirrhotic, and tumoral livers using in situ hybridization and immunohistochemistry. TGF-β1 type II receptors were detected on tissue sections using immunohistochemistry. In normal livers, TGF-β1 mRNA and protein were not significantly expressed. In cirrhotic nodules, a few sinusoidal cells and mesenchymal cells of fibrous septa displayed TGF-β1 mRNA. By immunohistochemistry, protein was detected in the extracellular matrix along the fibrous septa. Hepatocytes from normal and cirrhotic livers did not express TGF-β1. In contrast, the cytoplasm of hepatocytes in neoplastic nodules showed intense staining for TGF-β1 mRNA and protein. Although TGF-β1 receptor II was expressed on the plasma membrane of normal liver cells, tumoral hepatocytes no longer displayed membrane labeling but rather diffuse intracytoplasmic staining with perinuclear accumulation. This study suggests that the escape of tumoral hepatocytes from control of cell proliferation by TGF-β1, despite its overexpression by these cells, might be related to a defect in TGF-β1 receptor II processing on the liver cell membrane.     

TGF-β1 T869C Polymorphism May Affect Susceptibility to Idiopathic Pulmonary Fibrosis and Disease Severity

Background

Transforming growth factor-β₁ (TGF-β₁) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease.

Methods

We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T → C) of the TGF-β₁ gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques.

Results

The IPF patients consisted of 55 men and 30 women. The mean age was 61 ± 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO₂ and increased D(A–a)O₂ upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1–4.0, p = 0.028).

Conclusions

This study suggests that the TGF-β₁ gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-β₁ gene polymorphism and IPF.     

Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-β1 (TGF-β1)

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.     

Regulatory T Cell Subtypes and TGF-β1 Gene Expression in Chronic Allograft Dysfunction

Background: Regulatory T cells have been suggested to have a protective role against acute rejection in allograft recipients. However, there is little information available about their contribution to chronic rejection process. The role of transforming growth factor-beta 1 (TGF- β1) as a profibrogenic and/or immunoregulatory cytokine in renal allografts is also controversial. Objectives: To evaluate the frequency of CD4+CD25+CD127- and CD3+CD8+CD28- regulatory T cells in chronic allograft dysfunction (CAD) and to investigate the expression of TGF- β1 in renal allografts. Methods: Thirty biopsy-proven CAD patients were pair-matched with 30 stable graft function patients and a third group of healthy volunteers. Flowcytometry was performed on PBMCs to determine the frequency of CD3+CD8+CD28- and CD4+CD25+CD127- regulatory T cells in lymphocyt population. TGF- β1 gene expression was assessed by Real Time PCR. Results: The percentage of CD3+CD8+CD28- Tregs among renal allograft recipients was higher than healthy controls (p<0.001) since stable graft patients showed the most rates. The frequency of CD4+CD25+CD127- Tregs was lower in CAD patients than stable recipients (p=0.024) and healthy group (p=0.015). TGF- β1 gene expression was greater in CAD patients compared to healthy group (p=0.03) but there was no significant difference between gene expression of stable graft patients and healthy volunteers. Conclusion: The negative association between the frequency of regulatory T cell subtypes and chronic allograft dysfunction proposes these cells as probable candidates for promoting allograft survival. Moreover, despite the immunoregulatory capacity of TGF- β1, it is likely to be implicated in chronic damages of allograft tissue.     

Association between interleukin- 1β- 511( C/T) gene polymorphism and early diabetic kidney disease

<正>Objective To investigate the association between interleukin(IL)-1β-511(C/T)gene polymorphism and early diabetic kidney disease(EDKD)in Han population in Luzhou.Methods A total of 548 patients with type 2diabetes(T2DM)were enrolled in this study and divided into two groups:T2DM with normal albuminuria group(NA group,n=286)and T2DM with micro-albuminuria group(MA group,n=262).327 healthy subjects were     

TGF-β1基因T29→C多态性与2型糖尿病肾病的相关性

应用PCR-RFLP技术检测福建地区167例2型糖尿病患者（其中80例合并糖尿病肾病）和62名健康对照者TGF-β1基因T29→C多态性,结果显示,C等位基因可能与糖尿病肾病发病相关。     

转化生长因子(TGF-β1)在结核性胸膜炎的表达

结核性渗出性胸膜炎临床常见,如得不到早期合理治疗,容易引起胸膜肥厚、黏连或形成包裹性积液,从而影响肺的呼吸功能^[1]。临床上有通过胸腔内注药来减轻胸膜肥厚、黏连。现在收集我院2004年4月1日至2005年10月1日35例结核性胸膜炎患者,检测胸腔内注入异烟肼（0.1～0.2 g）、地塞米松（2～5mg）前后胸水中转化生长因子（TGF-β1）水平。探讨注药对胸水中TGF-β1表达的影响,寻求注药能减轻胸膜肥厚、粘连的理论依据。     

TGF-β1基因＋869T/C多态性与贵州汉族结核病易感性的关系

结核病的发病是一个多因素综合作用的结果,影响因素不仅包括感染结核菌的数量,毒力和宿主的防御反应,也包括种族、社会经济地位、年龄性别等因素。在影响宿主防御反应的遗传学因素中,基因的遗传多态性占有重要地位。因此,研究基因多态性与结核易感性的相关性对结核病的发病、预防、治疗及预后判断均有重要意义。肺结核病人血清中TGF-β水平比较高。     

TGF-β1-509C/T基因多态性与胃癌幽门螺杆菌感染的相关性

目的研究TGF-β1基因-509位点C/T多态性,探讨其与胃癌易感性及幽门螺杆菌感染的关系。方法采用聚合酶链反应-限制性片段长度多态性方法,检测80例胃癌患者与102例正常对照者TGF-β1基因-509位点C/T等位基因及基因型分布,并分析该基因多态性与胃癌幽门螺杆菌感染的相关性。结果胃癌组和正常对照组TGF-β1基因型频率无显著性差异;与正常对照组相比,胃癌组TGF-β1-509位点T等位基因频率显著增高(P=0.044,OR=1.550,95%C I=1.010~2.379)。胃癌患者TGF-β1基因型及等位基因频率与是否感染幽门螺杆菌无关。结论TGF-β1基因-509位点T等位基因可能是胃癌的遗传易感基因,而该位点基因多态性可能与是否感染幽门螺杆菌无关。     

罗格列酮影响肝纤维化大鼠转化生长因子β1(TGF-β1)表达的机制

目的探讨罗格列酮对大鼠肝纤维化的保护作用和对转化生长因子β1（TGF-β1）mRNA表达影响的机制。方法检测肝组织病理学改变；生化法检测肝功能指标；免疫组织化学技术检测TGF-β1、PPARγ在肝内的表达及定位；采用RT-PCR检测肝组织TGF-β1、PPAR-γ mRNA的表达。结果与模型组大鼠比较，干预组肝组织结构变化明显改善，纤维化增生程度减低，肝功能改善，大鼠肝内TGF-β1表达有所降低，并且大剂量组干预效果最为显著。结论罗格列酮能有效减轻肝纤维化大鼠的肝脏损伤及纤维化程度，其机制可能与PPAR-γ直接或间接抑制肝内TGF-β1 mRNA的表达有关。     

Colonic expression of Runx3 protein and TGF-β(1) and their correlation in patients with irritable bowel syndrome

ObjectiveTo investigate the role of Runx3 protein and TGF-β₁ in the pathogenesis of irritable bowel syndrome (IBS), as well as the correlation of these two proteins.MethodsColonic tissue was collected from patients with IBS and normal persons. The colonic expression of Runx3 protein and TGF-β₁ was detected with immunohistochemistry method. Semi-quantitative analysis was used to evaluate the staining degree of these two proteins.ResultsCompared with their counterparts, patients with IBS did not show any changes in the colonic expression of Runx3 protein and TGF-β₁ (P>0.05). Interestingly, there was a significant correlation between Runx3 protein and TGF-β₁ in patients with IBS(P<0.05).ConclusionsThe role of Runx3 protein and TGF-β₁ in the pathogenesis of IBS remains to be further studied.     

转化生长因子β(TGF-β)在肝纤维化中的作用

TGF-β可诱导肝星状细胞(HSC)合成纤维蛋白溶酶原活化因子抑制因子(PAI-1)和金属蛋白酶组织抑制剂(TIMP)而抑制基质金属蛋白酶的表达和活性,使ECM合成与降解紊乱,导致大量的ECM沉积于肝脏,引起肝的纤维化.     

TGF-β1与肝纤维化

肝纤维化是各种致病因子持续作用于肝脏,导致慢性肝损伤后的共同结果,多种细胞因子参与肝纤维化的发生,其中,转化生长因子β1(trarisforming growth factorβ1,TGF-β1)起关键性的作用.TGF-β1是具有多种生物学功能的细胞因子,可调节细胞的生长、分化、基质产生和凋亡;在胚胎生长发育过程中,对模型形成和组织特异性分化起重要作用;在成人,与组织修复和免疫系统调节过程有关.TGF-β1可以存在于所有的组织中,但在骨、肺、肾及胎盘组织中比较丰富.TGF-β1大多由实质细胞产生,亦可由浸润细胞,如淋巴细胞、单核细胞/巨噬细胞和血小板产生及释放.TGF-β1的信号转导由细胞膜上的是跨膜丝氨酸/苏氨酸激酶受体介导,在胞质内信号由递质Smads介导转导至细胞核,影响特异性基因表达.本文从TGF-β1的细胞来源、信号转导、激活肝星状细胞(hepatic stellate cell,HSC)、促进细胞外基质(extracellularmatrix,ECM)沉积和活性调节方面对其在肝纤维化的发生机制中的重要作用作一综述.     

TGF-β1及TGF-β1受体在胃癌及癌前病变中的表达

目的探讨ＴＧＦβ１与ＴＧＦβＩ受体（ＲⅠ）在胃癌发生发展中的作用．方法采用免疫组化ＳＰ法检测基本正常胃粘膜（３０例）、肠化生（３０例）、不典型增生（２２例）及胃癌（２５例）中ＴＧＦβ１与ＴＧＦβＲⅠ的表达．结果肠化生、不典型增生及胃癌中ＴＧＦβ１的表达增强而ＴＧＦβＲⅠ表达递减（Ｐ＜００５）;不典型增生组与胃癌组间ＴＧＦβ１表达无显著差异（Ｐ＞００５）;１９例胃癌（７６％）ＴＧＦβＲⅠ表达缺失;ＴＧＦβ１与ＴＧＦβＲⅠ表达与胃癌的浸润深度及淋巴结转移无关,在癌周正常组织与正常粘膜组间亦无显著差异（Ｐ＜００５）．结论ＴＧＦβＲⅠ表达缺失与ＴＧＦβ１过度表达可能参与胃癌的发生     

TGF-β1与糖尿病肾病

糖尿病肾病 (DN)是直接危害糖尿病患者生命的慢性并发症之一。迄今为止其发病机制尚未完全明了。目前 ,越来越多的研究表明 :转化生长因子 -β1 (TGF-β1 )可能在 DN的发病机制中占有重要地位 ,因此 ,对 TGF- β1 与 DN关系的研究有可能为诊治 DN提供新思路。一、TGF- β1 及其受体的生物学特征TGF- β在哺乳动物体内主要存在着 TGF- β1 、β2 、β3三种同分异构体。TGF- β1 的基因为 10 0 kb。内源性蛋白酶如呋林蛋白酶(furin)调控产生的 12 .5 KDa的 TGF- β单体以二硫键形成有功能的同源二聚体。各异构体的生物学特性基本…     

TGF-β1与糖尿病肾病

糖尿病肾病（DN）的基本病理改变首先是肾脏的肥大,继而出现肾小管、肾小球毛细血管基底膜增厚,小球系膜细胞与小管间质细胞外基质（ECM）沉积,最后出现典型的肾小球硬化性病变。近年来,转化生长因子β1（TGF-β1）在患者肾脏肥大、肾小球ECM沉积中的作用备受关注,本文就其与DN的关系综述如下。     

蛋白激酶C和TGF-β1在糖尿病大鼠肾脏中的表达

目的研究糖尿病大鼠肾小球中蛋白激酶C（PKC）活性变化和转化生长因子-β1（TGF-β1）的动态变化，探讨二者之间相互关系及其与糖尿病肾病（DN）发生发展的关系。方法用链脲佐菌素制备糖尿病大鼠实验模型，将大鼠随机分为正常对照组（N）、糖碌病2w组（DM2）和糖尿病4w组（DM4）。断头处死，分离肾小球，提取纯化胞浆及胞膜蛋白，利用（γ-32^P）-ATP底物磷酸化的方法检测胞浆及胞膜PKC括性。用免疫组织化学和400倍光镜检测TGF-β1在各组大鼠肾脏的表达。结果（1）糖尿病大鼠肾小球细胞内总的PKC活性与对照组无显著性差异，胞浆PKC活性略有下降，相差不显著；肾小球细胞膜PKC活性明显高于正常对照组，膜结合PKC百分比显著增加，且细胞膜PKC活性与肾脏肥大指数及Cer呈正相关。（2）糖尿病组TGF-β1的表达多于正常组。（3）肾小球细胞膜PKC活性与TGF-β1的表达正相关。结论高血糖慢性刺激可引起肾小球PKC活性增高，并诱导TGF-β1的表达。在糖尿病早期肾内血流动力学改变中发挥着重要的调控作用。     

Correlation of High Levels of Hyaluronan and Cytokines (IL-1β, IL-6, and TGF-β) in Ascitic Fluid of Cirrhotic Patients

Our objective was to investigate the relationship between endotoxin and hyaluronan synthesis and release in serum and ascitic fluid from cirrhotic patients. We studied hyaluronan, endotoxin, albumin, and creatinine levels in ascitic fluid and plasma and cytokine levels (IL-1, IL-6, TGF-) in ascitic fluid. TGF-, IL-6, and IL-1 correlation analyses indicated a strong dependence of the production of these cytokines on endotoxin levels. Correlation analyses for TGF- and IL-6 indicated a strong dependence of the production of hyaluronan on cytokine levels and, to a lesser extent, on IL-1 levels. Hyaluronan analysis indicated that a certain glycosaminoglycan level is required in ascites before its appearance in plasma. Our results disclosed elevated plasma hyaluronan concentrations. The simultaneous increased hyaluronan levels in ascitic fluid do not seem to be derived from the systemic circulation. In conclusion, the high hyaluronan-ascites/hyaluronan-plasma ratio suggests an intrinsic hyaluronan production from peritoneal cells induced by endotoxins.