Toll样受体4和肿瘤坏死因子αmRNA在动脉粥样硬化中表达的相关性研究

目的　探讨Toll样受体 4 (toll likereceptor 4 ,TLR4 )在动脉粥样硬化炎症过程中的作用。方法　应用核酸分子原位杂交技术检测 18例动脉粥样硬化斑块组织和 10例正常动脉组织中TLR 4和肿瘤坏死因子α(tumornecrosisfactorα,TNFα)mRNA的表达。并对二者的表达进行相关性分析。结果　TLR4和TNFαmRNA在动脉粥样硬化斑块组织中均有强烈表达 ,分别与正常对照组间差异有显著性意义 (TLR4 :t =8 94 5 ,P <0 0 0 1;TNFα :t =12 6 87,P <0 0 0 0 5 )。相邻切片的CD6 8染色证实TLR4和TNFα的阳性细胞主要为活化的巨噬细胞。且二者的表达呈正相关 (r =0 4 85 ,P <0 0 5 )。结论　TLR4通过上调TNFα的表达以促进动脉粥样硬化斑块炎症的活化 ,它可能是联接细菌感染与动脉粥样硬化炎症间的桥梁。     

Toll样受体4与动脉粥样硬化

炎症免疫反应是机体对微生物侵袭的天然防御反应，免疫细胞通过其细胞膜上的受体识别外来微生物的配体。从而启动宿主的炎症免疫反应。研究表明，动脉粥样硬化（atherosclerosis，As）是一种慢性炎症疾病，伴有免疫反应的炎症过程在As的发生和发展中起着决定性作用。但免疫反应在其中的分子生物学机制至今还未阐明。最近发现的Toll样受体（toll-like receptors，TLRs）是模式识别受体，能调节先天与获得性免疫，在抗微生物感染和识别内源性配体中起重要作用。TLRs识别内外源性配体后，启动炎性应答通路，诱导炎性因子大量产生，从而对机体组织产生保护和损伤作用。大量证据表明，TLRs在As中起着重要作用。本文就TLR4与As的相关研究作一综述。     

TLR4及相关信号通路在高血压发病机制中的作用研究进展

高血压是一种以动脉压增高为主要特点的临床综合征,易引发多种心脑血管疾病,已经成为影响人类身体健康的首要危险因素之一。随着对高血压发病机制研究的不断深入,TOLL样受体4(TLR4)可能在高血压的发生发展中发挥着重要作用。它识别配体后激活相关信号通路启动相关因子的表达,并通过肾素-血管紧张素(RAS)系统、氧化应激、内皮型一氧化氮合酶(eNOS)和NLRP3炎症小体参与高血压的发生发展过程。而针对TLR4及相关信号通路在高血压发病机制中的作用研究可能为高血压的临床治疗提供新的思路,使其成为高血压治疗的新靶点以及诠释中医药防治高血压机制的新内容。     

Toll样受体4和慢性炎症相关的代谢性疾病

Toll样受体(TLRs)家族是固有免疫中特异的Ⅰ型跨膜受体及病原模式识别受体(PRRs),通过与病原体相关分子模式(PAMPs)及内源性配体结合,激活信号转导通路,进而激发免疫反应.Toll样受体4(TLR4)是最早被发现的哺乳动物TLRs,近几年的研究表明,TLR4和慢性炎症及相关疾病关系密切.以下就TLR4与肥胖、2型糖尿病及动脉粥样硬化的关系做一综述.     

TLR2/4-IRF3信号通路调控胆固醇逆转运及其对动脉粥样硬化影响的研究进展

Toll样受体（toll like receptors,TLRs）是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要的作用,TLR2／4-IRF3信号通路对胆固醇逆转运的调控能对动脉粥样硬化易损斑块产生影响。本文就TLR2／4-IRF3信号通路如何调控胆固醇逆转运从而影响动脉粥样硬化的发生发展作一综述。     

血管平滑肌细胞TLR4与动脉粥样硬化发展关系的研究进展

目前动脉粥样硬化(AS)被认为是一种慢性炎症过程,Toll样受体4(TLR4)通过激活天然免疫,参与特异性免疫应答的启动,促进炎症的发展,在AS中发挥了重要作用。同时在AS发展过程中血管平滑肌细胞(VSMC)发生增殖、迁移,并分泌细胞因子、趋化因子、蛋白酶等,促进AS的发生、发展。此外,TLR4与VSMC之间存在一定的相互作用,对AS的不同阶段产生影响。     

TLR4激动上调内皮细胞氧化低密度脂蛋白受体LOX-1表达

目的近年研究表明介导先天免疫反应的受体Toll样受体4(TLR4)参与了动脉硬化的发生发展。业已证明氧化低密度脂蛋白受体LOX-1介导内皮细胞活化和功能失调，激发炎症过程，在动脉粥样硬化的发生和发展中起着极为重要作用。本研究观察TLR4激动是否调节内皮细胞LOX-1表达。方法应用脂多糖(LPS)刺激体外培养的人脐静脉内皮细胞(HUVECs)24h。采用RT—PCR和流式细胞术分别检测TLR4、LOX-1 mRNA和蛋白表达水平。为了观察转录因子NF—kB在调节LOX-1表达中的作用，应用NF-kB特异性抑制剂咖啡酸苯乙酯(CAPE)预处理细胞，然后以LPS刺激，检测LOX-1 mRNA和蛋白变化。结果LPS(10～1000ng／mL)上调HUVECs TLR4和LOX-1 mRNA表达，LPS(1000ng／mL)上调TLR4和LOX-1蛋白表达，CAPE(20μg／mL)可抑制LPS介导的LOX-1表达上调。结论TLR4／NF-kB信号途径可能通过上调内皮细胞LOX-1表达参与动脉粥样硬化的发生及发展。     

TLR4、TLR9与结直肠癌关系的研究进展

Toll样受体(Toll-like receptors,TLRs)是一组蛋白识别受体,能够识别微生物的成分并引起对抗微生物入侵的免疫应答。TLRs诱导的信号转导通路在肿瘤形成过程中起重要作用,TLR4和TLR9蛋白可能通过不同的信号转导途径促进肿瘤细胞增殖、抑制肿瘤细胞凋亡及免疫逃逸,它们是目前发现与肿瘤发病关系最密切的TLRs家族成员。TLR4与TLR9在大肠癌组织中的表达与结直肠癌细胞的分化程度、淋巴结转移及Dukes分期密切相关。本文就TLR4和TLR9蛋白参与结直肠癌发生、发展的相关机制及其在结直肠癌中的表达情况和临床意义作一概述。     

TLR4激动上调内皮细胞氧化低密度脂蛋白受体LOX-1表达

目的近年研究表明介导先天免疫反应的受体Toll样受体4(TLR4)参与了动脉硬化的发生发展.业已证明氧化低密度脂蛋白受体LOX-1介导内皮细胞活化和功能失调,激发炎症过程,在动脉粥样硬化的发生和发展中起着极为重要作用.本研究观察TLR4激动是否调节内皮细胞LOX-1表达.方法应用脂多糖(LPS)刺激体外培养的人脐静脉内皮细胞(HUVECs)24 h.采用RT-PCR和流式细胞术分别检测TLR4、LOX-1 mRNA和蛋白表达水平.为了观察转录因子NF-κB在调节LOX-1表达中的作用,应用NF-κB特异性抑制剂咖啡酸苯乙酯(CAPE)预处理细胞,然后以LPS刺激,检测LOX-1 mRNA和蛋白变化.结果LPS(10～1 000 ng/mL)上调HUVECs TLR4和LOX-1 mRNA表达,LPS(1 000ng/mL)上调TLR4和LOX-1蛋白表达,CAPE(20μg/mL)可抑制LPS介导的LOX-1表达上调.结论TLR4/NF-κB信号途径可能通过上调内皮细胞LOX-1表达参与动脉粥样硬化的发生及发展.     

Toll样受体在免疫紊乱中的作用

Toll样受体(Toll-like receptor,TLR)对先天性免疫有重要作用。个别的Toll样受体能识别积聚在病原体中的微生物成分。这种识别能促发必需的炎症免疫反应并诱发获得性免疫的活化。研究人编码TLR信号分子基因多态性,可以解释TLR与感染性疾病、动脉粥样硬化和免疫缺陷等人类疾病之     

Toll样受体与动脉粥样硬化

动脉粥样硬化是心脑血管疾病的病理基础,其发病机制备受关注但至今尚未阐明,包括天然免疫和获得性免疫在内的免疫机制在动脉粥样硬化中的作用不容忽视。Toll样受体是一类介导天然免疫的受体家族,近年来认为Toll样受体4与动脉粥样硬化的发生发展密切相关。现主要就Toll样受体的结构、分布及配体识别特点,特别是Toll样受体4与动脉粥样硬化的相关性研究作一综述。     

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-beta. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.     

Toll-like receptor 7 protects from atherosclerosis by constraining "inflammatory" macrophage activation

Background Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. Methods and Results We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe(-/-) mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C(hi) inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. Conclusions These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy.     

A functional toll-like receptor 8 variant is associated with HIV disease restriction

BACKGROUND: Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR8 has been found to recognize RNA derived from various viruses, including human immunodeficiency virus (HIV). Presently, very little is known about the influence of TLR8 genetic variation on susceptibility to and progression of HIV disease. METHODS AND RESULTS: We genotyped a population of 782 HIV-positive adults and 550 healthy control subjects for 3 nonsynonymous TLR8 single-nucleotide polymorphisms. We found that the presence of the most frequent TLR8 polymorphism, TLR8 A1G (rs3764880), confers a significantly protective effect regarding progression of the disease. In overexpression assays, we demonstrated that this receptor variant displays impaired NF-kappaB activation in vitro. Furthermore, we analyzed different cell types obtained from individuals differing in their TLR8 genotype and assessed their response to TLR8 ligands in vitro. The presence of the mutated receptor variant was associated with modulation of cytokine secretion profiles and lipid mediator synthesis patterns in monocytes and neutrophils. CONCLUSIONS: This first report of a functional TLR8 variant associated with a different clinical course of an RNA viral disease may have implications for the individual risk assessment of patients infected with HIV and other RNA viruses as well as for future HIV vaccine development.     

Enhanced expression of TLR4 in smooth muscle cells in human atherosclerotic coronary arteries

Toll-like receptors (TLRs) play an essential role in innate immunity as components of the primary defense system against microbial infections. It has become evident that TLRs are also involved in the pathogenesis of various cardiovascular diseases. However, the expression patterns of TLRs in the human coronary arteries of coronary artery disease (CAD) patients and the regulatory mechanisms of their expression remain unknown. The TLR4 expression patterns were invstigated by immunohistochemical analysis of coronary specimens obtained from autopsy cases or CAD patients by using directional coronary atherectomy. In atherosclerotic coronary arteries (n = 8), TLR4 immunoreactivity was colocalized with infiltrating inflammatory cells. Interestingly, vascular smooth muscle cells of atherosclerotic coronary arteries intensely expressed TLR4 even in the regions that had few inflammatory cells. In contrast, TLR4 expression was barely detected in the vascular smooth muscle cells of nonatherosclerotic coronary arteries (n = 4). Furthermore, intense expression of smooth muscle TLR4 was observed in the coronary arteries of CAD patients (n = 52). Stimulation with tumor necrosis factor α and angiotensin II increased the expression of TLR4 mRNA in cultured human vascular smooth muscle cells. Candesartan, an antagonist of the angiotensin II type 1 receptor (AT1), and N-acetylcystine inhibited angiotensin II-induced TLR4 mRNA expression in these cells. These findings suggest that the vascular smooth muscle cells of atherosclerotic coronary arteries may be activated to express TLR4. Furthermore, proinflammatory cytokines and oxidative stress in the inflammatory lesions might contribute to the enhanced expression of TLR4 in vascular smooth muscle cells of atherosclerotic arteries.     

The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases

Toll-like receptor 4 (TLR4) is a pattern recognition receptor that functions as lipopolysaccharide (LPS) sensor and whose activation results in the production of several pro-inflammatory, antiviral, and anti-bacterial cytokines. TLR4 is expressed in several cells of healthy liver. Despite the constant confrontation of hepatic TLR4 with gut-derived LPS, the normal liver does not show signs of inflammation due to its low expression of TLR4 and ability to modulate TLR4 signaling. Nevertheless, there is accumulating evidence that altered LPS/TLR4 signaling is a key player in the pathogenesis of many chronic liver diseases (CLD). In this review, we first describe TLR4 structure, ligands, and signaling. Later, we review liver expression of TLR4 and discuss the role of LPS/TLR4 signaling in the pathogenesis of CLD such as alcoholic liver disease, nonalcoholic fatty liver disease, chronic hepatitis C, chronic hepatitis B, primary sclerosing cholangitis, primary biliary cirrhosis, hepatic fibrosis, and hepatocarcinoma.     

载脂蛋白E基因敲除小鼠动脉粥样硬化斑块中血小板因子4和Toll样受体2的表达

目的观察高脂饲养的载脂蛋白E基因敲除小鼠动脉粥样硬化斑块表达Toll样受体2和血小板因子4的情况,探讨血小板因子4对内皮细胞Toll样受体2表达的影响。方法高脂饲料喂养载脂蛋白E基因敲除小鼠12周,建立动脉粥样硬化模型。安乐死处死动物,原位灌流固定,取主动脉于10%中性缓冲福尔马林中固定,石蜡包埋连续切片,HE染色观察动脉粥样硬化斑块形态,免疫组织化学检测斑块中Toll样受体2和血小板因子4的表达。结果载脂蛋白E基因敲除小鼠血脂水平明显增高,主动脉HE染色可见态动脉粥样硬化病变。在载脂蛋白E基因敲除小鼠主动脉富含脂质斑块中Toll样受体2表达上调,其中血管内皮细胞、巨噬细胞表达Toll样受体2明显增多。载脂蛋白E基因敲除小鼠主动脉斑块中也发现有血小板因子4表达,主要在内皮细胞和动脉粥样硬化斑块肩部。结论1.载脂蛋白E基因敲除小鼠粥样斑块中Toll样受体2表达上调,并且Toll样受体2主要表达在粥样斑块的内皮细胞和巨噬细胞上。2.载脂蛋白E基因敲除小鼠动脉粥样硬化斑块中可见血小板因子4表达。     

阿托伐他汀降低急性冠脉综合征患者外周血CD_(14)~+单核细胞表面TLR4的表达

目的 Toll 样受体4(TLR4)的激活与动脉粥样斑块的进展及斑块的不稳定导致临床并发症的发生有关。他汀类调脂药物临床获益可能与其调脂以外的作用尤其是抗炎作用有关,但抗炎作用的确切机制目前还不清楚。推测其抗炎作用可能是通过抑制 TLR4炎症信号通路起作用的。方法入选者为健康志愿者(n=22)及2006-07-2007-09在门诊和住院患者共121例[稳定性心绞痛(SAP)患者17例,急性冠脉综合征(ACS)患者82例],入院即刻抽取外周静脉血;将其中的41例 ACS 患者随机分为两组:在常规抗心绞痛治疗的基础上服用阿托伐他汀10 mg 组(20例)及阿托伐他汀40 mg 组(21例),治疗1月后抽取外周静脉血。观察指标为血脂、高敏 C 反应蛋白(hsCRP)、外周血 CD_(14)~+单核细胞表面 TLR4的表达,单核细胞表面 TLR4的表达采用流式细胞仪方法测定。结果 ACS 患者血 hsCRP 及外周血 CD_(14)~+单核细胞表面 TLR4的表达明显高于 SAP 患者(P<0.05)及正常对照组(P<0.05),hsCRP 与 TLR4的相关性分析结果是两者轻度相关(r=0.261,P=0.002)...     

Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages

The interaction of macrophages with Mycobacterium tuberculosis through Toll-like receptors is critical in defining the cytokine profile that may or may not control disease progression. Cell-wall lipids are the main pathogen-associated molecular ligands of mycobacteria, in this paper, we analysed how lipid fractions of three different strains of the M. tuberculosis complex (genotypes Canetti, Beijing and H37Rv) affected the innate immunity by regulating TNF-alpha and IL-10 secretion, TLR2, TLR4, and MHC class II expression of human monocyte-derived macrophages. Of note, lipid fractions from the Beijing genotype (hypervirulent phenotype) preferentially induced macrophages to secrete high amounts of TNF-alpha and IL-10, but downregulated TLR2, TLR4 and MHC class II expression. In contrast, lipids from M. tuberculosis Canetti induced lower amounts of TNF-alpha and IL-10, upregulated TLR2 and TLR4 without modifying MHC class II expression. These results indicate that the virulent mycobacterial genotype Beijing expresses lipids that negatively modified cytokine, TLR and MHC class II expression. These findings may help to unravel the complex mechanisms used by virulent mycobacteria to evade and subvert the immune response.