Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune response in the central nervous system (CNS) involves microglial cells which represent intraparenchymal antigen-presenting cells (APC). To control immune effector mechanisms it may be required to induce apoptosis of APC and thereby limit reactivation of T cells that have invaded the CNS. In the present study we investigated the susceptibility of primary murine microglia and of the murine microglial cell line BV-2 to undergo Fas-mediated apoptosis. Whereas resting microglia are resistant to Fas ligand (FasL) treatment, induction of FasL-mediated apoptosis was achieved by treatment with TNF-alpha or IFN-gamma. The effect of these cytokines was paralleled by up-regulation of Fas expression and down-regulation of Bcl-2 and Bcl-xL but not Bax. Activation of microglia by TNF-alpha and IFN-gamma was also accompanied by increased amounts of mRNA for the apoptosis inhibitor FLIP, an effect which did not protect the cells from FasL-induced apoptosis. The FasL-induced cell death pathway in microglia involves reactive oxygen intermediates because the antioxidants N-acetylcysteine and glutathione interfere with induction of apoptosis. Surprisingly, microglia constitutively express FasL on the cell surface. However, blocking of endogenous Fas-FasL interaction with Fas-Fc fusion protein did not enhance the survival of microglia, excluding the possibility of suicide or fratricide mechanisms. By their expression of FasL and their TNF-alpha/IFN-gamma-dependent sensitivity to the pro-apoptotic effect of exogenous FasL, microglial cells may influence the course of T cell-mediated diseases of the CNS.
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PMID:TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL. 986 77

Periodontitis is a chronic inflammatory disease which gradually destroys the supporting tissues of the teeth, leading to tooth loss in adults. The lesions are characterized by a persistence of inflammatory cells in gingival and periodontal connective tissues. To understand what mechanisms are involved in the establishment of chronic lesions, we hypothesized that infiltrating lymphocytes might be resistant to apoptosis. However, both Bcl-2 and Bcl-xL were weakly detected in lymphocytes from the lesions, compared with those from peripheral blood, suggesting that these cells are susceptible to apoptosis. Nevertheless, very few apoptotic cells were observed in tissue sections from the lesions. Lymphocytes from the lesions expressed mRNA encoding Fas, whereas Fas-ligand mRNA was very weakly expressed in lymphocytes from the lesions and in periodontal tissues. Since the results indicated that lymphocytes in the lesions might be susceptible to Fas-mediated apoptosis but lack the death signal, we next investigated if these lymphocytes actually undergo apoptosis by the addition of anti-Fas antibodies in vitro. Fas-positive lymphocytes from the lesions underwent apoptosis by these antibodies, but Fas-negative lymphocytes and Fas-positive peripheral lymphocytes did not undergo apoptosis by these antibodies. These results indicate that lymphocytes in the lesions are susceptible to activation-induced cell death and are induced to die by apoptosis after the addition of exogenous Fas ligand.
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PMID:In vitro induction of activation-induced cell death in lymphocytes from chronic periodontal lesions by exogenous Fas ligand. 1002 94

Binding of agonistic anti-Fas (APO-1/CD95) antibodies or Fas ligand (Fas-L) induces apoptosis in some Fas+ leukemias, and anti-Fas antibody was originally investigated as a possible therapeutic reagent. More recently, a number of studies have examined a potential role for the Fas/Fas-L pathway in chemotherapy-induced apoptosis as well as the effect of Bcl-2 on this pathway. These studies are briefly reviewed here.
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PMID:The clinical significance of Fas expression in leukemia: questions and controversies. 1002 85

Cigarette smoking has been shown to affect human immune responses. We have studied Fas/Fas ligand (FasL) expression, which is involved in the cytotoxic activity, immune privilege, and self-tolerance, and other apoptosis-associated molecule expression of peripheral blood lymphocytes (PBL) in healthy subjects with/without cigarette smoking. We found that expression of FasL protein was detected marginally in the fresh PBL and was induced upon mitogen activation in normal individuals without smoking. In contrast, fresh PBL from those with chronic cigarette smoking exhibited enhanced expression of FasL protein without in vitro mitogen stimulation. Moreover, mitogen stimulation failed to augment FasL protein expression of their lymphocytes, suggesting dysregulation of FasL expression of PBL in individuals with cigarette smoking. In contrast, Fas, Bcl-2, and p53 expression were not significantly different between normal individuals with chronic cigarette smoking and those without smoking. In addition, we found that in vitro brief treatment with nicotine induces and/or enhances FasL mRNA and protein expression of lymphocytes from normal donors without smoking. These results suggest that aberrant FasL expression of lymphocytes is, at least in part, involved in the immune impairment in individuals with chronic cigarette smoking.
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PMID:Effects of cigarette smoking on Fas/Fas ligand expression of human lymphocytes. 1006 46

Apoptosis is an energy-requiring mechanism of cell death which is a physiological event in organ morphogenesis, clone selection of lymphoid cells and cell turnover, but also occurs in many pathological conditions. It is under genetic control, bcl-2 being the major apoptosis suppressing gene, while p53 and c-myc are apoptosis promoting genes. Other factors, such as the Fas/Fas1 system, the caspases cascade, cytokines and enzymes also play a role in determining apoptosis. The term apoptosis was introduced by Kerr to describe this type of death in ischaemic rat liver, and the same Councilman bodies are now considered an example of apoptotic death. Virus-infected hepatocytes bear Fas receptors and apoptosis is induced by binding to the Fas ligand which is expressed by activated T cells; this action is probably mediated by enzymes of the caspase family and/or by granzyme B. The Fas/Fas1 system is also involved in apoptosis occurring in chronic non suppurative destructive cholangitis, in transplant rejection and in other liver diseases, including neoplasms; in the latter Bcl-2 protein and mutations of p53 also seem to play an important role. Cytokines are also frequently involved. Toxins like alcohol probably induce apoptosis by producing active oxidants. Whether aging enhances apopstosis in liver is still controversial. Although many molecular mechanisms have been suggested to be involved the switch on/off of apoptosis is still poorly understood and will be a matter of further investigations.
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PMID:Liver and apoptosis. 1009 Nov 8

Recent studies have shown that with the onset of sepsis there is an increase in apoptosis (Ao) in the thymus, mediated in part by steroids, which may contribute to a loss of T-cell progenitors, thereby, reducing immune functions. However, reports also suggest that these steroid effects could be mediated by Fas ligand (FasL) and/or by endotoxin (ETX). Thus, our study was to determine: 1) if polymicrobial sepsis (cecal ligation and puncture; CLP) alters thymocyte Fas antigen/receptor (Fas+) expression and 2) if the increase in Ao in septic ETX-sensitive C3H/HeN mice is seen in thymocytes from ETX-tolerant, C3H/HeJ, or the FasL-deficient/ETX-tolerant, C3H/HeJ-FasL(gld), male mouse strains subjected to CLP or sham-CLP (Sham) 12 or 24 h before they were killed. The results of flow cytometric analysis indicated that increased %Ao+ seen in thymocytes of CLP C3H/HeN mice was associated with either no change (12 h) or a decrease in %Fas+ expression at 24 h, although the %Bcl-2+ (an antiapoptotic protein) cells was depressed at both times. Additional studies examining C3H/HeJ or C3H/HeJ-FasL(gld) mice subjected to CLP show that as with the ETX-sensitive mouse, thymocyte Fas and Bcl-2 antigen expression as well as Bcl-2/Bcl-X(L/S) mRNA levels decreased although the %Ao+ increased after CLP in both ETX-tolerant and ETX-tolerant/FasL-deficient mice. Furthermore, if ETX-tolerant/FasL-deficient CLP animals were administered the steroid receptor antagonist RU-38486 (s.c., immediately after CLP) the increase in Ao was markedly attenuated, along with restoration of the percentage of cells expressing Bcl-2 and Fas antigen as well as Bcl-2/Bcl-X(L/S) mRNA levels. Thus, we concluded that increased septic thymocyte Ao is not regulated through either Fas mediated pathway or ETX, but is a result of the release of endogenous steroids possibly acting directly or indirectly on Bcl-2 expression.
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PMID:Does Fas ligand or endotoxin contribute to thymic apoptosis during polymicrobial sepsis? 1018 75

Cancer cells often resist Fas-mediated apoptosis even when the Fas receptor is expressed at the cell surface. We show here that human and rat colon cancer cells undergo massive apoptosis when they are exposed to soluble Fas ligand in the presence of sodium butyrate, an agent that induces by itself only a low rate of apoptosis. Sodium butyrate potentiates Fas-dependent apoptosis in seven out of eight colon cancer cell lines. Sodium butyrate does not increase Fas receptor cell surface expression and does not modify cell levels of Bcl-2, Bcl-xL, Bcl-xS and Bax. Sodium butyrate also induces tumor cell sensitization to the apoptotic effect of the combination of TNF-alpha and IFN-gamma, but it does not modify the level of the FADD/Mort1 adaptator molecule, at the connection between Fas- and TNF-dependent apoptosis pathways. Because the clinical toxicity of butyrate is low, its ability to enhance Fas-signal delivery in cancer cells could be of therapeutic interest.
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PMID:Cancer cell sensitization to fas-mediated apoptosis by sodium butyrate. 1020 Apr 99

In this study, we investigate Fas ligand expression in the human endometrium during the menstrual cycle in relation to Fas antigen and Bcl-2 expression, using immunoelectron microscopy and Western blotting. Endometrial samples were obtained from 54 pre-menopausal non-pregnant women who underwent laparotomies for benign diseases. The Fas ligand, as well as the Fas antigen, were expressed on the surface of endometrial glandular cells throughout the menstrual cycle, whereas Bcl-2 showed a cyclic expression pattern, peaking during the late proliferative phase. A noteworthy finding was that both the Fas ligand and the Fas antigen were localized on Golgi apparatuses and vesicles, in addition to the cell membranes, during the late proliferative phase. These results indicate that the Fas ligand and Fas antigen which are localized on Golgi apparatus and vesicles during the late proliferative phase are incorporated into the cell membranes during the secretory phase, and are co-expressed on the cell membranes of endometrial glands throughout the menstrual cycle. The factors regulating Fas-mediated apoptosis in the human endometrium, including the level of expression of the Fas ligand and Bcl-2 are discussed.
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PMID:Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle. 1032 8

In order to determine the mechanism of tumour destruction by tumour-infiltrating lymphocytes (TIL), we examined the ability of both CD4+ and CD8+ effector TIL, and TIL clones, to manifest granzyme-mediated and Fas-mediated destruction of tumour targets. In many in vitro studies TIL have been shown to manifest anti-tumour reactivity, yet many tumours escape immunological destruction. To investigate the role of Fas expression and the concomitant sensitivity to the inducibility of apoptotic death, we derived TIL from four melanomas and one glioma. The glioma, and all but one of the melanomas, expressed Fas, but Fas-mediated apoptosis could only be detected if the targets were treated with cyclohexamide. The melanomas and the glioma all expressed detectable cytoplasmic Bcl-2 protein, known to exert anti-apoptotic activity. Lysis of tumours by CD8-enriched cultures and CD8+ clones was Ca2+-dependent and could not be modified by an anti-Fas MoAb. In CD4-enriched cultures or CD4+ clones with cytotoxic potential against tumour cells, cytotoxicity was also Ca2+-dependent. As Ca2+-dependent cytotoxicity is usually the result of secretion of perforin/granzyme-B, we investigated the presence of perforin in cytotoxic CD4+ clones and demonstrated the presence of granular deposits of this enzyme in some of the CD4+ clones. Although an anti-Fas MoAb did not block the lysis of melanoma targets by CD4+ clones, the examination of Fas-dependent targets demonstrated that these clones also had the potential to kill by the Fas/Fas ligand system. These data suggest that the predominant mechanism in tumour killing by TIL appears to be perforin-granzyme-dependent, and that the solid tumour cell lines we studied are less susceptible to Fas-mediated apoptosis. As non-apoptotic pathways may enhance tumour immunogenicity, exploitation of the perforin-granzyme-dependent cytotoxic T lymphocyte (CTL) pathways may be important for achieving successful anti-tumour responses.
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PMID:Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes. 1036 Dec 24

Memory T cells respond in several functionally different ways from naive T cells and thus function as efficient effector cells. In this study we showed that primed T cells were more resistant to Fas-mediated activation-induced cell death (AICD) than naive T cells using OVA-specific TCR transgenic DO10 mice and Fas-deficient DO10 lpr/lpr mice. We found that apoptosis was efficiently induced in activated naive T cells at 48 and 72 h after Ag restimulation (OVA peptide; 0.3 and 3 microM), whereas apoptosis was not significantly increased in activated primed T cells at 24-72 h after Ag restimulation. We further showed that the resistance to AICD in primed T cells was due to the decreased sensitivity to apoptosis induced by Fas-mediated signals, but TCR-mediated signaling equally activated both naive and primed T cells to induce Fas and Fas ligand expressions. Furthermore, we demonstrated that primed T cells expressed higher levels of Fas-associated death domain-like IL-1beta-converting enzyme inhibitory protein (FLIP), an inhibitor of Fas-mediated apoptosis, at 24-48 h after Ag restimulation than naive T cells. In addition, Bcl-2 expression was equally observed between activated naive and primed T cells after Ag restimulation. Thus, these results indicate that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period.
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PMID:Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells. 1041 29


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