Fas/FasL系统与心肌缺血再灌注细胞凋亡

心肌缺血再灌注损伤与众多凋亡基因密切相关.Fas/FasL系统在心肌缺血再灌注损伤中起关键作用,是引起细胞凋亡的主要途径之一,是直接启动细胞凋亡信号传导的系统之一.Fas/FasL系统与心肌缺血再灌注细胞凋亡及其信号传导机制是目前国内外研究的热点,现对该问题做一综述.     

Fas／Apo-1（CD95）系统与大肠癌

Fas／Apo-1(CD95)系统与机体免疫和细胞凋亡(apontosis)关系十分密切,其诱导细胞凋亡的作用早在1991年就已被肯定。细胞凋亡是多细胞机体为调控机体发育,维护内环境稳定,由基因调控的细胞主动死亡过程。目前发现细胞凋亡不仅调节着细胞生长与更新的平衡稳定,而且在相关基因参与下与大肠癌的发生发展密切相关。现对Fas／FasL诱导细胞凋亡功能以及其与大肠癌的关系综述如下。     

Fas、FasL与1型糖尿病

1型糖尿病是T细胞介导的自身免疫性疾病 ,β细胞凋亡在其发病中起了一定作用 ,Fas/FasL系统参与 β细胞凋亡。Fas是死亡因子 ,FasL是其受体 ,表达Fas的细胞和表达FasL的细胞或抗Fas抗体结合均可导致表达Fas的细胞凋亡。正常胰腺细胞不表达Fas,胰岛炎时 ,许多细胞因子和炎症介质可诱导胰岛β细胞表达Fas,从而被表达FasL的细胞 (T细胞或胰岛α及 β细胞 )诱导凋亡 ,导致糖尿病的发生。对Fas/FasL研究可能在 1型糖尿病免疫预防上具有潜在的应用前景。     

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     

Fas／FasL与消化系统疾病

Fas/FasL系统是指细胞表面的“死亡受体”及其配体分子,是引起细胞凋亡的主要机制。肝和胃肠道的许多细胞可表达Fas/FasL,且在多种肝脏和胃肠道疾病的发病机制中起重要作用。     

Fas/FasL在急性胰腺炎肝损伤中的作用

Fas/FasL介导的凋亡参与急性胰腺炎肝损伤的发生发展,急性胰腺炎上调肝内的促凋亡通路并且促使肝细胞损伤和肝细胞凋亡.急性胰腺炎时通过上调Kupffer细胞内FasL生成的信号使FasL表达增加,FasL激活Fas相关的死亡域和暴露死亡效应结构域,随后活化Caspase级联反应和下游的效应Caspases,最终导致DNA裂解和肝细胞凋亡,从而介导肝损伤.本文就Fas/FasL结构、分布、功能及介导急性胰腺炎肝损伤的机制作一综述.     

Fas/FasL系统与结核病

Fas/FasL抗原系统是重要的细胞凋亡信号传导系统 ,在抵抗结核分枝杆菌入侵中对维持宿主自身稳定起重要调控作用。近年来 ,人们对Fas/FasL抗原系统及其在结核病的发生、发展中的作用有了进一步的了解 ,对结核病的发病机制有了全新的认识 ,现综述如下。一、Fas/FasL系统自 1972年Kerr提出细胞凋亡 (apoptosis)的概念后 ,1989年Trauth等[1] 才首次报道了死亡因子Fas(APO 1,CD95)的发现。 1991年Itoh等[2 ] 发现了Fas的相应配体FasL(Fasligand ,CD95L)的存在 ,Fas可与FasL组成死亡起始信号复合物 (deathinitiatingsignallingcomplex…     

Fas/FasL与消化系统疾病

Fas/FasL系统是指细胞表面的“死亡受体”及其配体分子,是引起细胞凋亡的主要机制。肝和胃肠道的许多细胞可表达Fas/FasL,且在多种肝脏和胃肠道疾病的发病机制中起重要作用。     

细胞凋亡在肾脏疾病中的研究进展

细胞凋亡（apoptosis）又称程序化细胞死亡（programmed cell death，PCD），是多细胞有机体为调控机体发育、维护内环境稳定，由基因控制的细胞主动死亡过程。细胞内外的凋亡诱导因素通过多种信号转导机制来调控细胞凋亡过程，其中Fas／FasL信号系统是重要的凋亡信号转导系统之一，Fas是细胞表面Ⅰ型跨膜蛋白，Fas配体（Fas ligand，FasL）为Ⅱ型跨膜蛋白，FasL或特异性Fas抗体与Fas相互作用可导致细胞凋亡。大量事实表明，细胞凋亡参与了肾脏正常发育及肾疾病发生等多个过程，在肾脏疾病的发生发展过程中发挥着有益或有害的作用。     

Fas/FasL在中枢神经系统免疫炎症反应中的作用

Fas/FasL系统是重要的细胞凋亡信号转导系统.FasL诱导Fas阳性细胞凋亡及其机制已得到众多研究的肯定.近年来的研究发现,中枢神经系统缺血、变性、感染等多种疾病的免疫炎症病理过程中均伴有FasL和Fas水平的增高,同时诱导一些细胞因子的释放,提示Fas/FasL在中枢神经系统免疫炎症的调节中起着莆要作用,日此作用不依赖于细胞凋亡途径.文章对其在中枢神经系统免疫炎症方面的研究进展做了综述.     

Induction of Fas (CD95/APO-1) ligand is essential for p53-dependent apoptosis in an in vitro renal carcinoma model system

Purpose The Fas/CD95/APO-1 ligand (FasL) is a death cytokine that binds to cell surface Fas/CD95/APO-1 receptor, yet a possible role of FasL expression in p53-dependent apoptosis is not fully understood in many human malignancies, including renal carcinoma. Methods By Northern blot and Western blot analyses, we determined the effect of p53 on the FasL and Fas receptor expression. To do this, we employed an in vitro renal carcinoma model system that was previously established by stably co-transfecting a temperature-sensitive mutant allele of the p53 tumor suppressor (ts-p53) with either the c-Myc oncogene or adenovirus E1A oncogene in baby rat kidney (BRK) epithelial cells. The ts-p53 is activated only at a permissive temperature. The transactivation activity of p53 was assessed by luciferase reporter assays. The sub-G1 cell population in the cell cycle representing apoptotic cell death was measured by flow cytometric analysis. Results We found that the level of endogenous FasL, but not Fas receptor, was increased at a permissive temperature with delayed kinetics when compared with p21WAF1 expression, but was coincident with p53-induced apoptosis, whereas an apoptosis-defective mutant p53, which lacks the PxxP region (P: Proline, x: any amino acid), failed to induce FasL expression and hence apoptosis. Notably, p53-induced apoptosis was completely blocked by overexpressing a dominant negative inhibitor of the FADD/Mort-1, a pro-apoptotic adaptor that lies immediately downstream of the FasL/Fas receptor. Conclusions These results suggest that the FasL is a critical downstream effector of p53-dependent apoptosis in a cultured BRK renal carcinoma model system.     

Mechanism of counterattack of colorectal cancer cell by Fas/Fas ligand system

AIM: To determine the role of Fas/Fas ligand (FasL) in the immune escape of colon cancer cells. METHODS: Immunohistochemistry was used to observe the expression of Fas and FasL in the tissues of colon cancer patients. In situ hybridization was used to detect the localization of FasL mRNA expression in cancer tissues. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay and CD45 staining were performed to detect the apoptosis of tumor-infiltrating lymphocytes (TILs). Co-culture assays of colon cancer cells (SW480) and Jurkat cells (Fas-sensitive cells) were performed to observe the counterattack of colon cancer cells to lymphocytes. RESULTS: Of 53 cases of colon carcinomas, 23 cases (43.4%) expressed Fas which was significantly lower as compared to the normal colonic mucosa (73.3%, P<0.01), and 45 cases (84.9%) of colon carcinomas expressed FasL, whereas only two cases (3.75%) in normal mucosa expressed FasL. FasL expression in the colon cancer cells was found to be associated with increased cell death of TILs. The apoptotic rate of TIL in the FasL-positive staining regions of tumor cells was significantly higher than that in the FasL-negative staining region (54.84±2.79% vs 25.73±1.98%, P<0.01). The co-culture of SW480 cells and Jurkat cells confirmed the function of FasL on the SW480 cells. The apoptotic rates of Jurkat cells were found to be related with the amount of SW480 cells. CONCLUSION: Colon cancer cells can escape the immune surveillance and killing via decreasing Fas expression, and can counterattack the immune system via increasing FasL expression. Fas/FasL can serve as potential targets for effective antitumor therapy.     

Thymineless death in colon carcinoma cells is mediated via Fas signaling

Fas is expressed constitutively in colonic epithelial cells and is also expressed in colon carcinomas and in cultured colon carcinoma cell lines. However, the potential role of Fas signaling in mediating apoptosis in cells of this type remains unknown. We have developed human colon carcinoma cell models deficient in thymidylate synthase that demonstrate acute (TS⁻ cells) or delayed (Thy4 cells) apoptosis following DNA damage induced by thymineless stress. Complete protection of cells from acute apoptosis and prolongation of delayed apoptosis was obtained following exposure to the NOK-1 monoclonal antibody (inhibitory to Fas signaling) during the period of dThd deprivation. These results suggested that apoptosis induced by thymineless stress was regulated by autocrine signaling via Fas–FasL interactions. Fas expression was high in both TS⁻ and Thy4 cells. However, FasL, undetectable in synchronous cultures, was up-regulated in TS⁻ cells at 48 hr, when cells were undergoing acute apoptosis, and in Thy4 cells at 96 hr, correlating with the delayed onset of thymineless death. FasL expression also correlated with acute apoptosis induced in parental GC₃/cl cells, commencing at 48 hr, following thymidylate synthase inhibition by 5-fluorouracil/leucovorin exposure. Fas-mediated apoptosis induced by the cytotoxic anti-Fas monoclonal antibody CH-11 was inhibited following adenoviral delivery of a Bcl-2 cDNA, and Bcl-2 also protected cells from acute apoptosis induced by dThd deprivation. Taken together, these data demonstrate a functional Fas system in these cultured colon carcinoma cell models, and they demonstrate that Fas–FasL interactions can link DNA damage induced by thymineless stress to the apoptotic machinery of colon carcinoma cells.     

羊栖菜多糖诱导MCF-7细胞凋亡机制的研究

目的 研究羊栖菜多糖对MCF-7细胞凋亡的诱导作用及对凋亡相关基因表达的影响，探讨藻类多糖的抗肿瘤机理。方法 流式细胞仪观察SFPS对肿瘤细胞周期及细胞凋亡的影响；RT-PCR法检测凋亡相关基因Fas，FasL mRNA的表达。结果 羊栖菜多糖可阻滞MCF-7细胞由G0／G1期进入S期，升高细胞凋亡指数(APO)；同时上调Fas，FasL mRNA的表达。结论 羊栖菜多糖可能通过上调凋亡相关蛋白Fas，FasL的表达，促进肿瘤细胞凋亡达到治疗肿瘤的目的。     

Fas/FasL系统与心肌细胞凋亡

心肌细胞凋亡是许多心血管疾病发生发展的重要机制。Fas／FasL系统作为细胞凋亡的信号传导系统也参与了心肌细胞凋亡。当表达Fas的靶细胞和活性细胞的FasL交联后，启动Fas／FasL死亡信号传导系统，分别激活神经鞘磷脂途径蛋白酶途径和DAxx途径而引起Fas表达阳性的靶细胞凋亡。大量研究表明，Fas／FasL系统参与了急性心肌梗塞、病毒性心肌炎、扩张型心肌病、风湿性心脏病、心律失常、心脏移植排斥反应和心力衰竭等心肌细胞凋亡。因此对Fas／FasL系统某一环节的干预为心血管疾病的防治开辟一个新的涂释。     

Differential effects of membrane and soluble Fas ligand on cardiomyocytes: role in ischemia/reperfusion injury

Cardiomyocyte apoptosis by Fas ligand (FasL)/Fas signaling is associated with various pathophysiological conditions, such as ischemia/reperfusion injury and congestive heart failure. In this study, we tested the hypothesis that shedding of membrane FasL is a mechanism for downregulating FasL/Fas signaling and both membrane and soluble FasL are involved in cardiomyocyte hypoxia/reoxygenation (H/R) injury. We also examined the relative importance of mitochondrial damage and direct cleavage of the executioner caspases by activated initiator caspase 8 in the propagation of FasL/Fas signaling activated by either recombinant membrane FasL or H/R. We demonstrated that in neonatal rat cardiomyocytes maintained under normal culture conditions, recombinant human soluble FasL increased caspase 3 activation by twofold but did not reduce cell viability. In contrast, infection with a recombinant adenoviral vector expressing the non-cleavable human FasL (Ad2/nchFasL) resulted in cardiomyocyte death that was attenuated by soluble FasL. H/R increased the mRNA levels of both FasL and Fas and activated caspases 8, 9 and 3, indicating the activation of FasL/Fas signaling. Z-IETD.fmk and Z-LEHD.fmk, selective inhibitors for caspases 8 and 9, respectively, abolished caspase 3 activation induced by Ad2/nchFasL or H/R. Z-IETD.fmk also significantly reduced Ad2/nchFasL- or H/R-induced cardiomyocyte death. H/R potentiated membrane FasL-induced cell death. These results suggest that shedding of membrane FasL downregulates FasL/Fas signaling in cardiomyocytes and both membrane and soluble FasL contribute to H/R injury. Activation of FasL/Fas signaling by either recombinant membrane FasL under normal culture conditions or H/R causes cardiomyocyte death mainly through the mitochondrial damage/caspase 9 activation pathway.     

Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack

The mechanisms by which esophageal tumors escape immunologic recognition and clearance are only partly understood at the molecular level. Esophageal cancers have been shown to evade host recognition by down-regulation of antigen presentation and production of immunosuppressive factors. Recently, two independent reports have shown that esophageal tumor cells abundantly express Fas ligand (FasL) in vivo. As the triggering agonist for Fas receptor (Fas or APO-1/CD95)-mediated apoptosis of lymphocytes, FasL normally plays immune down-regulatory roles, including activation-induced cell death of T and B cells, as well as maintaining immune privilege in certain organs. Fas ligand expressed by esophageal cell lines has been shown to induce apoptosis of cocultured Fas-sensitive lymphoid cells in vitro. FasL expression by esophageal carcinomas in vivo has been associated with significantly reduced tumor-infiltrating lymphocytes (TILs) in FasL-positive tumor nests, concomitant with significantly increased TIL apoptosis in these nests. These studies support a 'Fas counterattack' mechanism of immune escape in esophageal cancer. By expressing functional Fas ligand, esophageal cancer cells can deplete antitumor lymphocytes by inducing apoptosis. To express functional FasL, esophageal carcinomas also acquire molecular mechanisms to resist autocrine Fas-mediated apoptosis of tumor cells.     

Fas ligand expression in colon cancer： A possible mechanism of tumor immune privilege

AIM: To detect the expression of Fas ligand (FasL) in colon cancer tissues and cell lines and analyze the function of FasL-expressing colon cancer cells in inducing Fas-sensitive T lymphocyte apoptosis. METHODS: Ninety surgically resected colon cancer tissues and 15 hepatic metastasis specimens were investigated by immunohistochemical method with normal colon mucosa and colon adenoma as control. The relationship between FasL expression and pathologic features was also analyzed. FasL expression of 4 colon cancer cell lines, SW620, Lovo, LS-174T and SW1116, were detected by Western blotting assay. The function of FasL expressed on colon cancer cells was determined by coculture assay with Jurkat T lymphocytes, the apoptotic rate of which was detected by flow cytometry assay. RESULTS: Fifty-six (62.22%) cases of all the 90 colon cancer tissues and all (100%) the liver metastasis specimens expressed FasL, significantly higher than normal colon mucosa and colonic adenoma. Higher expression of FasL was found in more advanced stage of colon cancer and in cancer tissues with lymphatic or hepatic metastasis. All the colon cancer cell lines were found to express FasL. After coculture with the SW1116 cells for 24 h with an effector: target ratio 10:1, the rate of apoptosis of Jurkat cells rose from 1.9% to 21.0%. CONCLUSION: The expression of FasL is upregulated in colon cancer and the functionally expressed FasL can induce apoptosis of Fas-expressing T lymphocytes.