TRAIL在树突状细胞杀伤肿瘤细胞中的作用及其机制的研究

ＴＮＦα相关的凋亡诱导配体 (ＴＮＦα -ｒｅｌａｔｅｄａｐｏｐｔｏｓｉｓｉｎｄｕｃｉｎｇｌｉｇａｎｄ ,ＴＲＡＩＬ)是ＴＮＦ家族中与ＣＤ95Ｌ同源性最高的新型凋亡分子 ,与ＣＤ95Ｌ一样 ,能够诱导多种肿瘤细胞的凋亡 ;但与ＴＮＦα、ＣＤ95Ｌ不同的是 ,它对机体正常组织不具有明显的毒性作用 ,只选择性地杀伤肿瘤细胞或转化细胞 ,由于这个特点 ,它目前在肿瘤免疫研究中倍受重视。ＴＲＡＩＬ分子有 4个膜受体 ,其中包括 ,两个有完整的胞浆内段、能够介导凋亡信号、诱导细胞凋亡的死亡受体 (ｄｅａｔｈｒｅｃｅｐｔｏｒ,ＤＲ) ,即ＤＲ4、…     

线粒体在B细胞受体介导的凋亡过程中的关键性作用

细胞凋亡对组织发育和自身稳定具有重要调节作用。为了阐明Ｂ细胞受体 (ＢＣＲ)介导的凋亡机制 ,研究者用人Ｂｕｒｋｉｔｔ淋巴瘤细胞株ＢＬ6 0做为研究生发中心Ｂ细胞耐受的实验模型。实验结果指出 :①ＴＮＦ相关凋亡诱导配体 (ＴＲＡＩＬ)的两种受体 ,即ＴＲＡＩＬ Ｒ1 、 Ｒ2 ,以及ＣＤ95、ＴＮＦ Ｒ1 、 Ｒ2 和ＴＮＦ Ｒ相关凋亡介导蛋白 (ＴＲＡＭＰ)等死亡受体或ＴＮＦ受体 ,均不参与ＢＣＲ介导的ＢＬ6 0细胞凋亡 ;②上述死亡受体或ＴＮＦ受体介导的凋亡依赖于Ｃａｓｐａｓｅ 8的早期活化 ,随后发生Ｃａｓｐａｓｅ 3等的活化。而该研…     

TNF相关的凋亡诱导配体及其受体与凋亡

ＴＮＦ相关的凋亡诱导配体（ＴＮＦ－ｒｅｌａｔｅｄ ａｐｏｐｔｏｓｉｓ－ｉｎｄｕｃｉｎｇ ｌｉｇａｎｄ，ＴＲＡＩＬ）是新发现的ＴＮＦ超家族成员，与新近发现的受体（ＴＮＦ－ｒｅｌａｔｅｄ ａｐｏｐｔｏｓｉｓ－ｉｎｄｕｃｉｎｇ ｌｉｇａｎｄ ｒｅｃｅｐｔｏｒ，ＴＲＡＩＬＲ）相结合的启动细胞内的信号转导，在体外迅速诱导各种来源的细胞株的凋亡，本文综述了ＴＲＡＩＬ和ＴＲＡＩＬＲ结构功能的分子基础及其诱导凋亡     

肺癌患者血清TNF、SA、IL-8含量及其临床意义

肿瘤坏死因子 (Ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒ,ＴＮＦ)是一种有效的肿瘤细胞杀伤因子 ,而且是机体炎症反应和免疫应答的重要调节因子[1] ;ＳＡ早年已被认为是肿瘤细胞所分泌 ,并将其作为肿瘤标志而应用于临床[2 ] ;ＩＬ - 8主要由单核细胞和巨噬细胞所产生[3 ] ;近年的研究表明 ,ＴＮＦ、ＳＡ、ＩＬ - 8与肿瘤的发生、发展以及预后有着密切的关系。本文报告肺癌患者血清中ＴＮＦ、ＳＡ、ＩＬ - 8水平 ,并就其临床意义作初步探讨 ,现将结果报告如下。对象和方法一、对象 :(一 )正常人 :35人 (男 2 0 ,女 15 )。均为我院预防保健科…     

LPS、rh-TNFα刺激PBL诱导TRAIL表达的初步研究

选择人ＰＢＬ作为人ＴＲＡＩＬ基因的来源,抽提细胞在ＬＰＳ和ｒｈ－ＴＮＦα刺激２,１０,１８ｈ的总ＲＮＡ,通过ＲＴ６－ＰＣＲ观察ＴＲＡＩＬ基因转录ｍＲＮＡ的水平,然后用ＰＣＲ扩增ＴＲＡＩＬ基因,并用免疫印迹法分析ＴＲＡＩＬｍＲＮＡ翻译蛋白的水平。结果发现：在ＬＰＳ和ｒｈ－ＴＮＦα刺激细胞并进一步诱导细胞凋亡可能与诱导表达ＴＲＡＩＬ有关。     

肺癌、结肠癌中Fas配体“假”受体的基因扩增

Ｆａｓ 配体（ＦａｓＬ）由激活的Ｔ细胞和ＮＫ细胞产生,它通过死亡受体Ｆａｓ诱导靶细胞发生细胞凋亡。本研究发现了一种可溶性的ＦａｓＬ的“假”受体－ＤｃＲ３（ｄｏｃｏｙ ｒｅｃｅｐｔｏｒ ３）,它可通过与ＦａｓＬ结合从而抑制ＦａｓＬ介导的细胞凋亡。 作者从胎肺中分离出一段未知的ｃＤＮＡ序列,它和ＴＮＦＲ基因超家族具有同源性,其编码的多肽约含３００个氨基酸,并在Ｎ－末端的先导序列后紧邻有４个保守的半胱氨酸富集区,这一特点与ＴＮＦＲ家族成员非常相似。与ＴＮＦＲ的同源体Ｐｓｔｅｏｐｒａｔｅｇｅｒｉｎ（ＯＰＧ）…     

重组可溶性TRAIL在大肠杆菌中的表达、分离纯化 及其诱导肿瘤细胞凋亡活性的研究

目的和方法 :本项研究建立了高效稳定表达可溶型ＴＲＡＩＬ(ｒｓＴＲＡＩＬ ,ＴＮＦ -ｒｅｌａｔｅｄａｐｏｐｔｏｓｉｓｉｎｄｕｃｔｉｎｇｌｉｇａｎｄ)重组融合蛋白的工程菌 ,并进行了该重组融合蛋白的表达、分离纯化及诱导肿瘤细胞凋亡活性的研究。结果 :重组融合蛋白在大肠杆菌中的表达产量可达到菌体总蛋白的 30 %左右 ,亲和层析纯化后 ,重组融合蛋白的纯度可达 95%以上。其表现分子量约为 2 2ｋＤ ,等电点为 6 2 9,Ｎ -末端的氨基酸顺序与理论值相同。该融合蛋白在浓度为 0 1～ 1 μｇ/ｍＬ时 ,能显著诱导所试全部 7种肿瘤细胞株细…     

囊性纤维变性跨膜调节器基因突变对男性生殖的影响

1　ＣＦＴＲ基因突变及主要症状囊性纤维变性跨膜调节器 (ｃｙｓｔｉｃｆｉｂｒｏｓｉｓｔｒａｎｓ ｍｅｍｂｒａｎｅｃｏｎｄｕｃｔａｎｃｅｒｅｇｕｌａｔｏｒ,ＣＦＴＲ)基因于 1989年被发现 ,位于人的第 7染色体上。其编码的蛋白是一种膜蛋白 ,这种跨膜蛋白是一个Ｃｌ- 离子通道蛋白 ,受ｃＡＭＰ的调控。正常的ＣＦＴＲ由 14 80个氨基酸组成 ,含有两个结构区 ,每个结构区含有 6个跨膜片段[1] ,由称为Ｒ -结构域的多肽链连接 ,Ｒ -结构域上有大量的磷酸化位点 ,还有两个核苷酸结合位点(ｎｕｃｌｅｏｔｉｄｅｂｉｎｄｉｎｇｆｏｌｄｓ ,Ｎ…     

Th1/Th2细胞亚群的特异性表面标志及其鉴定

198 6年Ｍｏｓｍａｎｎ等[1 ] 根据Ｔ辅助淋巴细胞(ＣＤ4)分泌的细胞因子谱 (ｃｙｔｏｋｉｎｅｐｒｏｆｉｌｅｓ)的不同 ,将ＣＤ4细胞分为Ｔｈ1和Ｔｈ2亚群。Ｔｈ1细胞主要分泌γ -干扰素 (ＩＦＮ -γ)、白细胞介素 - 2 (ＩＬ - 2 )和肿瘤坏死因子 - β(ＴＮＦ - β) ,介导细胞免疫应答 ;而Ｔｈ2细胞主要分泌ＩＬ - 4、ＩＬ - 5、ＩＬ - 1 0及ＩＬ -1 3等因子 ,促进抗体的产生 ,介导体液免疫反应。在多数免疫反应中 ,Ｔ辅助淋巴细胞并不产生典型的Ｔｈ1或Ｔｈ2细胞和因子 ,而主要是由Ｔｈ0细胞分泌的混合型的细胞因子。但在疾病的状态下 ,Ｔ…     

风湿性关节炎患者治疗前后血清TNF、SlL—2R、SA联检的临床意义

肿瘤坏死因子 (Ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒ,ＴＮＦ)是一种有效的肿瘤细胞杀伤因子 ,而且是机体炎症反应和免疫应答的重要调节因子[1] 。白细胞介素 - 2受体为一具有多种生理学活性的细胞因子 ,在细胞免疫、体液免疫和免疫调节中起着十分重要的作用[2 ] 。血清唾液酸 (ＳＡ)早年认为是肿瘤细胞所分泌 ,并将其作为肿瘤标志物[3 ] 。近年的研究表明[4] ,ＳＡ在一些非肿瘤疾病患者中亦有不同程度的升高。本文报告风湿性关节炎患者治疗前后血清ＴＮＦ、ＳＩＬ - 2Ｒ、ＳＡ含量的变化 ,并就临床意义作初步探讨 ,现报告如下。对象和方…     

The role of TNF related apoptosis-inducing ligand in neurodegenerative diseases

A hallmark of all forms of neurodegenerative diseases is impairment of neuronal functions,and in many casesneuronal cell death.Although the etiology of neurodegenerative diseases may be distinct,different diseases displaya similar pathogenesis,for example abnormal immunity within the central nervous system(CNS),activation ofmacrophage/microglia and the involvement of proinflammatory cytokines.Recent studies show that neurons in aneurodegenerative state undergo a highly regulated programmed cell death,also called apoptosis.TNF-relatedapoptosis-inducing ligand(TRAIL),a member of the TNF family,has been shown to be involved in apoptosisduring many diseases.As one member of a death ligand family,TRAIL was originally thought to target only tumorcells and was not present in CNS.However,recent data showed that TRAIL was unregulated in HIV-1-infected andimmune-activated macrophages,a major disease inducing cell during HIV-1-assoeiated dementia(HAD).TRAIL isalso induced on neuron by β-amyloid protein,an important pathogen for Alzheimer's disease.In this review,wesummarize the possible common aspects that TRAIL involved those neurodegenerative diseases,TRAIL inducedapoptosis signaling in the CNS cells,and specific role of TRAIL in individual diseases.Cellular & MolecularImmunology.2005;2(2):113-122.     

Following TRAIL's path in the immune system

The members of the tumour necrosis factor (TNF) superfamily of cytokines play important roles in the regulation of various immune-cell functions. Likewise, induction of cell death by apoptosis is indispensable for the normal functioning of the immune system. There are two major pathways of apoptosis induction. The intrinsic, or mitochondrial, pathway is regulated by the activation and interaction of members of the Bcl-2 family. The extrinsic, or death receptor, pathway is triggered by certain TNF family members when they engage their respective cognate receptors on the surface of the target cell. Hence, cell-to-cell-mediated death signals are induced by activation of these death receptor–ligand systems. Besides TNF itself and the CD95 (Fas/APO-1) ligand (FasL/Apo1L), the TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the subfamily of ligands that is responsible for extrinsic induction of cell death. Depending on their status of stimulation, TRAIL can be expressed by various cells of the immune system, amongst them natural killer (NK) cells, T cells, natural killer T cells (NKT cells), dendritic cells and macrophages. TRAIL has been implicated in immunosuppressive, immunoregulatory and immune-effector functions. With respect to pathological challenges, TRAIL and its receptors have been shown to play important roles in the immune response to viral infections and in immune surveillance of tumours and metastases. In this review we summarize the current knowledge on the role of TRAIL and its receptors in the immune system and, based on this, we discuss future directions of research into the diverse functions of this fascinating receptor–ligand system.     

To die or not to die--the quest of the TRAIL receptors.

The last 18 months have witnessed the characterization of several new members of the tumor necrosis factor (TNF) receptor family. Among these are five receptors for the cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand). Two of these receptors, TRAIL-R1 and TRAIL-R2, contain classical cytoplasmic death domains and are able to transduce an apoptotic signal. The others lack functional death domains and are not able to promote cell death. Indeed, one of the receptors for TRAIL, osteoprotegerin (OPG) is a soluble protein whose activities so far have been shown to be inhibition of osteoclastogenesis and increased bone density in vivo. The existence of multiple receptors for TRAIL suggests an unexpected complexity to TRAIL-mediated biological functions.     

Surface expression of TRAIL/Apo-2 ligand in activated mouse T and B cells

Like other members of the TNF family, TRAIL/Apo-2 ligand induces apoptosis in sensitive target cells in a caspase-dependent fashion. We recently found that TRAIL may be constitutively expressed on the surface of mouse and human tumor cells of T and B origin. To define the pattern of TRAIL expression in normal immune cells, freshly isolated splenocytes, Concanavalin A/IL-2-activated T cells and lipopolysaccharide-activated B cells were analyzed by surface staining with or without secondary stimulation. Activated, but not resting, CD3⁺ cells expressed TRAIL in an activation-dependent fashion. Conversely, freshly isolated B220⁺ cells displayed surface TRAIL and CD95L that were retained following activation. Restimulation with the protein kinase C activator phorbol 12-myristate 13-acetate and the calcium ionophore ionomycin or an agonistic anti-CD3 monoclonal antibody induced significant up-regulation of surface TRAIL and CD95L in CD3⁺ , TCRα β cells with CD4⁺ or CD8⁺ phenotype. Similarly to CD95L, TRAIL up-regulation was protein synthesis dependent and cyclosporin A sensitive. These results indicate that both TRAIL and CD95L are displayed on the cell surface of activated immune cells and may thus represent complementary effector pathways in the regulatory functions of T and B cells.     

2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.

TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential, we have determined the crystal structure of human TRAIL. The structure reveals that a unique frame insertion of 12-16 amino acids adopts a salient loop structure penetrating into the receptor-binding site. The loop drastically alters the common receptor-binding surface of the TNF family most likely for the specific recognition of cognate partners. A structure-based mutagenesis study demonstrates a critical role of the insertion loop in the cytotoxic activity of TRAIL.     

Current understanding on the immunological functions of tumor necrosis factor-related apoptosis-inducing ligand

Tumor necrosis factor （TNF）-related apoptosis-inducing ligand （TRAIL） selectively induces apoptosis in various tumor cells and virus-infected cells, but rarely in normal cells. The killing specificity of TRAIL has brought great interests to develop a novel apoptosis-based anti-tumor agent for clinical application. TRAIL is expressed in many normal tissues and cells, such as liver, brain, kidney, heart, colon, lung, and testis. However, immunological and physiological functions of TRAIL in vivo have not been understood well. In the present paper we summarized the progress in the research on immunological functions of TRAIL.     

Monocytes stimulated with group B streptococci or interferons release tumour necrosis factor-related apoptosis-inducing ligand

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytotoxic member of the TNF family. Some reports have shown that TRAIL is released from cells in a soluble form. In this work, we have investigated the mechanism of release of TRAIL from monocytes. First, we show that whole gram-positive, gram-negative and mycoplasmal bacteria as well as lipopolysaccharide (LPS), interferon-alpha (IFN-alpha), -beta and -gamma all induced upregulation of TRAIL on the surface of human monocytes. Next, we show that IFN-alpha, -beta and -gamma all induced a dose-dependent release of TRAIL, giving significant amounts of soluble TRAIL after 2 days. Of the bacteria, only the Group B streptococcus COH-1 (GBS) induced release of TRAIL and concomittantly induced IFN-alpha. Monocytes stimulated with GBS or IFN-alpha also showed extensive cell death. When monocyte apoptosis was prevented by interleukin-1, GM-CSF, LPS or the caspase inhibitor zVADfmk, the IFN-alpha-induced release of TRAIL was reduced, whereas agents inducing necrosis caused increased release of TRAIL. LPS also prevented release of TRAIL from GBS-stimulated monocytes. The release of TRAIL from IFN-alpha-stimulated monocytes was reduced by inhibitors of both cysteine and metalloproteases. We conclude that bacteria and IFN induce upregulation of membrane TRAIL and that release of TRAIL is associated with cell death.     

Tuning the rheostat of the myelopoietic system via Fas and TRAIL

During the last decade, the concerted effort of numerous scientific groups has expanded our understanding of the finely tuned network present within bone marrow for the regulation of the hematopoietic system. This network, comprising humoral and cellular cross talk, is responsible for the adaptation of hematopoietic populations to demands as they arise. Major components of this control system are death receptors and their specific ligands, which eliminate superfluous cells once they have fulfilled their respective functions. The important role of Fas (CD95/Apo-1), one member of this death receptor family, in the regulation of T- and B-cell functions has been established. Alteration of Fas expression and/or function in lymphoid cells may contribute to the development of autoimmunity and/or neoplastic diseases. In addition to controlling lymphoid compartments, Fas is also involved in the regulation of myeloid cell functions. More recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its specific receptors (TRAIL-R) have been identified as further members of this death receptor/ligand family. The TRAIL-R/TRAIL system is of vital importance for the maturation and functioning of immune effector cells of lymphoid, as well as myeloid, origin. In the present review, we have summarized current knowledge about both death receptor/ligand systems in the expansion and functioning of cells from the myeloid compartments, highlighted their role in normal hematopoiesis, and assessed their alterations in pathologic or neoplastic conditions.     

TNF ligands and receptors in autoimmunity: an update

Over two decades of research have increased the interest in factors from the tumor necrosis factor family. The vast majority of these factors are powerful modulators of critical immune functions and participate in pathogenic mechanisms leading to autoimmune disease. This field constantly evolves with the addition of new family members and the discovery of their function. During the past few years several additional factors from this family, such as BAFF, RANKL, TRAIL and GITRL, have emerged with novel functions that regulate both T and B cell immune tolerance and participate in tissue destruction in autoimmunity. These new findings revealed exciting innovative strategies for the treatment of autoimmune diseases.     

Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways,targets, and therapeutic tools

In the past decade, it was concluded from a number of investigations that death domain-containing members of the tumor necrosis factor-receptor (TNF-R) family and their ligands such as Fas/FasL and TNF-related apoptosis-inducing ligand (TRAIL)-R/TRAIL are essential for maintaining an intact immune system for surveillance against infection and cancer development and that nondeath domain-containing members such as CD30 or CD40 are involved in the fine tuning of this system during the selection process of the lymphatic system. In line with this conclusion are the observations that alterations in structure, function, and regulation of these molecules contribute to autoimmunity and cancer development of the lymphoid system. Besides controlling size and function of the lymphoid cell pool, Fas/FasL and TRAIL-R/TRAIL regulate myelopoiesis and the dendritic cell functions, and severe alterations of these lineages during the outgrowth and expansion of the lymphoid tumors have been reported. It is the aim of this review to summarize what is currently known about the complex role of these two death receptor/ligand systems in normal, disturbed, and neoplastic hemato-/lymphopoiesis and to point out how such knowledge can be used in developing novel, therapeutic options and the problems that will have to be faced along the way.