FasL,Fas介导的细胞凋亡与肝脏疾病

细胞凋亡、或程序性细胞死亡(PCD)是机体在生长、发育及维持内部平衡过程中发生的正常细胞的生理性死亡现象。近来研究证实FasL(Fas配体)与Fas是介导细胞凋亡的一对膜蛋白。FasL、Fas以膜分子或可溶性分子的形式存在,与参与其信号途径调控的许多细胞内外因子共同组成Fas系统,在维持组织正常发育、控制免疫反应、调节机体生理平     

凋亡基因Fas系统与心力衰竭

近年的研究表明,细胞凋亡是慢性心力衰竭(心衰)发生、发展的重要机制,而Fas作为凋亡信号传导途径的重要基因,在心衰患者心肌细胞凋亡过程中起着重要的调控作用,故血清sFas与sFasL可以反映心肌细胞凋亡与心衰的严重程度.     

Fas抗体介导的嗜酸细胞凋亡及其清除机制

目的探讨Fas单抗对嗜酸细胞(EOS)凋亡的诱导作用及凋亡EOS的清除机制。方法分离正常人外周血EOS,加入白细胞介素(IL)5与不同浓度(1～1000ng/ml)Fas单抗培养,台盼蓝拒染法和末端标记法分别检测细胞存活和凋亡变化,观察凋亡EOS能否被巨噬细胞(MΦ)吞噬。结果Fas单抗对IL-5介导的EOS存活呈浓度和时间依赖性抑制作用。高浓度的IL-5(106U/L)不能抑制Fas单抗的作用。Fas单抗(100ng/ml)处理24h后EOS即有明显的凋亡［（35±6）%］,72h后增至(96±3)%,前后比较差异有显著性（P<0.01）。Fas单抗(100ng/ml)处理24、48和72h的EOS与MΦ培养,吞噬凋亡EOS的阳性MΦ百分率分别为(20±5)%、(38±6)%和(45±6)%,MΦ吞噬新分离的EOS阳性百分率为（1±2）%,与前者比较差异均有显著性（P<0.01）。结论Fas抗体能有效诱导EOS凋亡,凋亡EOS能被MΦ所吞噬清除。     

Fas／FasL介导的凋亡与自身免疫性甲状腺病

Ｆａｓ／ＦａｓＬ诱导的细胞凋亡在机体的发育,生长,内环境稳定方面起重要作用。下沉甲状腺细胞表达Ｆａｓ;Ｇｒａｖｅｓ病患者ＩｇＧ可显著下调甲状腺细胞Ｆａｓ的表达,此可能与Ｇｒａｖｅｓ甲亢时甲状腺肿大有关;桥本甲状腺炎时甲状腺细胞表达Ｆａｓ增强,但ＦａｓＬ的表达结果有所不,     

Caspase与胰岛β细胞凋亡的关系

半胱天冬蛋白酶（caspase）可通过Fas、肿瘤坏死因子、颗粒酶B、Bcl-2家族等通路激活,参与β细胞凋亡.不同的caspase在β细胞凋亡中所起的作用不尽相同.Caspase-8与caspase-3作为启动酶与效应酶分别在凋亡信号转导途径的上游与下游起重要作用,经过一系列酶联反应,最终引起β细胞发生凋亡的特征性形态学改变.     

加强Fas和Fas配体的研究

加强Ｆａｓ和Ｆａｓ配体的研究贾克明Ｆａｓ是人体多种细胞表面的一种膜蛋白，具有３２５个氨基酸，Ｆａｓ基因位于人体第１０对染色体。Ｆａｓ配体（Ｆａｓｌｉｇａｎｄ或ＦａｓＬ）也是细胞表面的一种膜蛋白，具有２１８个氨基酸，其基因位于人体第１对染色体。当某一细...     

Caspase与缺血性脑血管病

Ｃａｓｐａｓｅ是细胞凋亡程序中一类关键的同源半胱氨酸蛋白酶，特异性在天门冬氨酸残基后裂解靶蛋白。当细胞表面死亡受体被激活或细胞内死亡信号存在时，始动ｃａｓｐａｓｅ活化并引发下游效应ｃａｓｐａｓｅ蛋白水解激活的级联反应，最终使一系列细胞及细胞修复酶等蛋白裂解，导致细胞凋亡。脑缺血后，ｃａｓｐａｓｅ ｍＲＮＡ及蛋白水平升高，酶活性增强，引起神经元凋亡；而抑制ｃａｓｐａｓｅ活性可减轻脑缺血损伤。如果与超     

Caspase与胰岛β细胞凋亡的关系

半胱天冬蛋白酶(caspase)可通过Fas、肿瘤坏死因子、颗粒酶B、Bcl-2家族等通路激活,参与β细胞凋亡。不同的caspase在β细胞凋亡中所起的作用不尽相同。Caspase-8与caspase-3作为启动酶与效应酶分别在凋亡信号转导途径的上游与下游起重要作用,经过一系列酶联反应,最终引起β细胞发生凋亡的特征性形态学改变。     

Fas/FasL介导的凋亡在桥本病发病机制中的作用

用免疫组织化学法和Westem印迹法在24例桥本病(HT)甲状腺组织中观察到甲状腺细胞Fas表达增高，Fas／FasL介导的细胞凋亡参与HT的发病。     

白藜芦醇对动脉粥样硬化兔Fas/FasL凋亡途径的影响

目的:探讨白藜芦醇对兔动脉粥样硬化斑块内细胞凋亡及Fas、FasL、Caspase-3基因转录的影响.方法:成熟健康雄性新西兰白兔70只,适应性喂养10 d后随机分为5组:A组继续喂普通饲料;B组喂高脂饲料;C、D、E组喂高脂饲料的同时分别给予白藜芦醇4 mg·kg~(-1)·d~(-1)、8 mg·kg~(-1)·d~(-1)、16 mg·kg~(-1)·d~(-1)进行干预.末端脱氧核苷酸转移酶介导的脱氧三磷酸尿苷缺口末端标记法(TUNEL)检测细胞凋亡;逆转录聚合酶链式反应法(RT-PCR)检测Fas、FasL、Caspase-3mRNA转录水平.结果:高脂喂养12周后,成功建立动脉粥样硬化模型;病理对照组斑块内有大量的凋亡细胞;与病理对照组比较,正常对照组血管内膜偶见少量的凋亡细胞(P<0.01),低至高剂量白藜芦醇干预组细胞凋亡依次降低(P<0.05),其Fas mRNA、FasL mRNA转录水平也依次降低,白藜芦醇高剂量组Fas mRNA转录水平与正常对照组比较差异无统计学意义(P>0.05).结论:白藜芦醇可抑制动脉粥样斑块内细胞凋亡,从而稳定斑块、抑制动脉粥样病变进展,这一作用可能通过抑制Fas/FasL凋亡途径,降低Caspase-3基因转录来实现,并具有一定的量效关系.     

Ethanol-induced apoptosis in polarized hepatic cells possibly through regulation of the Fas pathway

BACKGROUND: It has been noted that alcohol-related liver diseases can be associated with an increase in apoptotic hepatocellular death. Moreover, the promotion of hepatocyte apoptosis may be linked to signals emanating from death receptors, particularly Fas [CD95/apoptosis-inducing protein 1 (APO-1)]. In the present study, we utilized an in vitro hepatic culture model [hybrid of human fibroblast (WI 38) and rat hepatoma (Fao) cells, WIF-B cells] to study potential contributing mechanisms involved in hepatocellular apoptosis following ethanol administration. METHODS: WIF-B cultures (differentiated hepatic cells that efficiently metabolize alcohol) were treated with or without ethanol and specific inhibitors of alcohol metabolism and cysteine protease activity, followed by morphological and biochemical examination of proapoptotic parameters. RESULTS: The results of this work demonstrated that ethanol administration leads to an increase (45%-60%) in caspase-3 activity and that the induction of apoptosis was found to be linked to the metabolism of alcohol. Additionally, increases were observed in the activity of upstream initiator caspases (caspase-2 and caspase-8) that are directly related to membrane signaling events of death receptors such as Fas. Moreover, it was determined that the activation of caspase-3 could be blocked by the presence of a specific caspase-8 inhibitor, again linking death receptor-associated proteases to downstream effector caspase activity in alcohol-related death. Finally, ethanol administration was found to result in an increase in the amount of Fas protein present in the membrane fraction of the cell. The increase in membrane Fas protein indicates ligand-independent membrane targeting of Fas in the alcohol-treated cells that could potentially be a key signaling event in the induction of the proapoptotic caspase cascade. CONCLUSIONS: The data presented here indicate that alcohol metabolism induces apoptosis in WIF-B cells that occurs, in part, by mechanisms involving signals emanating from death receptors.     

Fas/FasL系统表达与结直肠癌的研究进展

细胞凋亡是指在一定生理和病理情况下,机体为维护内环境的稳定而发生的主动性细胞死亡过程,即程序性死亡.由死亡受体与其配体相互作用是引起细胞凋亡的主要途径之一,其中Fas/FasL系统是被认为最主要的介导细胞凋亡的信号转导途径.大肠癌是严重威胁人类健康的常见恶性肿瘤之一,大肠癌的发生、发展与细胞凋亡的调节失衡有关.本文就Fas/ FasL系统表达与结直肠癌发生发展的关系及相关方面研究作一综述.     

Fas ligand and Fas receptor are coexpressed in normal human esophageal epithelium: a potential mechanism of apoptotic epithelial turnover

Fas (CD95/Apo-1) receptor (FasR) is a cell-surface receptor that mediates apoptotic cell death upon triggering by Fas ligand (FasL). We sought to determine whether normal human esophageal epithelial cells express FasL and/or FasR and whether their localization is consistent with a role in the turnover of normal esophageal epithelium. Normal esophageal epithelium was immunohistochemically positive for FasL in upper prickle cell layers and in mature squamous cells, but the proliferative basal layer was negative. FasL mRNA was detected in the same epithelial cell layers by in situ hybridization. Co-localization of FasL mRNA and protein therefore confirmed that FasL expression is induced in esophageal epithelial cells as they reach terminal differentiation. FasR was immunohistochemically detected throughout the esophageal epithelium. Positive TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling) staining confirmed cell death of the FasL and FasR coexpressing mature epithelial cells. CD45-positive immunocytes were notably absent from FasL-expressing upper epithelial layers. The findings are consistent with a contributory role for Fas-mediated autocrine suicide or paracrine fratricide in the apoptotic turnover of normal esophageal epithelium.     

Fas and Fas ligand-mediated apoptosis and its role in autoimmune diabetes

The relationship between Fas-mediated apoptosis and Type 1 diabetes is currently under investigation. Fas/Fas ligand interaction could be involved both in the insulitis process and in β-cell death. Nevertheless, different mechanisms appear to be involved in human Type 1 diabetes and in NOD mice. In the present work, we review recent evidence of the role of the Fas/Fas ligand system in human and NOD mouse diabetes, describing possible hypotheses for its involvement in the pathogenesis of the disease, with possible implications for therapy and islet transplantation. Copyright © 1998 John Wiley & Sons, Ltd.     

Fas／Fas—L在重型肝炎患者肝组织中的表达及其在肝细胞凋亡中的意义

目的 研究Fas/Fas-L系统在重型肝炎患者肝细胞中的表达情况及在肝细胞凋亡中的意义。方法 采用免疫组织化学方法对20例住院的重型肝炎病人之活检肝组织进行了Fas抗原及Fas配体表达的检测,并运用末端转移酶标亡技术（TUNEL）同时检测细胞原位凋亡的情况。结果 所检测20例重型肝炎肝组织中,Fas抗原在肝细胞中呈强阳性表达;浸润的淋巴细胞上大量表达Fas-L,肝细胞中也有散在分布;敏例标本均见凋亡细胞,分布在炎症坏死区及周边和小叶内。结论 Fas/Fas-L系统过量表达,引起大量肝细胞死亡,参与重型肝炎的发病,Fas途径引起的细胞凋亡可能是重型肝炎发病过程中的重要机制之一。所检标本中,凋亡和坏死同时存在,这两种不同的死亡方式有重型肝炎的发病上存在着关联性。     

Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway

Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in susceptible cells. To characterize the molecular events involved in Fas-induced apoptosis, we examined the contribution of two subgroups of the mitogen-activated protein (MAP) kinase family, the Jun kinases or stress-activated protein kinases (JNKs/SAPKs) and the extracellular signal-regulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. Here we show that both JNK and ERK protein kinases were activated upon Fas crosslinking through a Ras-dependent mechanism. Interference with either the JNK or ERK pathway by ectopic expression of dominant-interfering mutant proteins blocked Fas-mediated apoptosis. ERK activation was transient and associated with induced expression of the Fas receptor. In contrast, JNK activation was sustained and correlated with the onset of apoptosis. These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas. Inhibition of Fas killing by an interleukin 1β-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation upon Fas ligation. In contrast, changes in Bcl-2 level due to expression of sense and antisense vectors influenced the sensitivity to Fas killing and Fas-induced JNK activation.     

丙型肝炎肝组织Fas配体的免疫组化研究

以免疫组化法研究Ｆａｓ配体（Ｌ）在丙型肝炎病人肝组织内的表达情况，发现在碎屑样坏死（ＰＮ）、桥样坏死（ＢＮ）及灶性坏死性浸润的单个核细胞有明显的ＦａｓＬ表达，阳性率为４１．２％。ＦａｓＬ阳性细胞与肝脏炎症分级程度密切相关，Ｇ０－１组与Ｇ３－４组比较有显著差异。ＦａｓＬ在肝细胞内亦有表达，表达程度似与炎症程度有关。不论是Ｆａｓ或ＦａｓＬ在慢性丙肝中的表达均较急性肝炎显著，提示在病程慢性化中可能起着重     

An aggressive nasal lymphoma accompanied by high levels of soluble Fas ligand

Fas ligand (FasL), either in the membrane bound form or soluble form, has cytotoxic activity against Fas-expressing cells. We report a case of nasal lymphoma accompanied by liver damage and pancytopenia. The serum level of soluble FasL (sFasL) was very high on admission, but rapidly decreased to normal levels after chemotherapy for lymphoma. Liver damage and pancytopenia also improved with the decrease in serum sFasL. Since Fas is expressed on both hepatocytes and haemopoietic cells, these facts suggest that FasL was expressed on lymphoma cells and directly associated with pathogenesis of liver damage and pancytopenia through its cytotoxic activity.