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)

Apoptosis is a required event in maintaining kinetic homeostasis within continually renewing tissues such as skin. However, no systematic study of the apoptotic process in epidermal keratinocytes of the skin has been performed. In this report, we examined the expression of proteins associated with promoting (Fas) or preventing (Bcl-2, Bcl-x, CD40) apoptosis in the normal, psoriatic, and malignant keratinocyte. Immunohistochemical staining and flow cytometry analysis revealed that normal cultured keratinocytes express low levels of Fas, CD40, and Bcl-x that was enhanced by cytokines including gamma-interferon (IFN-gamma) and a phorbol ester tumor promoter, TPA. Only faint Bcl-2 staining was detected in cultured keratinocytes exposed to IFN-gamma and TPA compared with the prominent expression of Bcl-x. Biopsies of normal skin, psoriatic plaques, and basal cell carcinomas were examined to extend the in vitro observations. Immunohistochemical staining revealed that while keratinocytes in normal epithelium express low to absent levels of Fas and Bcl-x, psoriatic keratinocytes expressed significantly higher levels of Fas and Bcl-x. In contrast, malignant keratinocytes in basal cell carcinomas expressed high levels of Bcl-2, but minimal Bcl-x, and no Fas. Immunoblot analysis revealed that the long form of Bcl-x (Bcl-xI), which prevents apoptosis in lymphocytes, is expressed by cultured keratinocytes and psoriatic plaque keratinocytes. We conclude that normal cytokine-activated keratinocytes can express an apoptotic (Fas) and an anti-apoptotic protein (Bcl-x). The overexpression of Bcl-x in psoriasis, or Bcl-2 in basal cell carcinomas, may contribute to the longevity of these cells by blocking the normal apoptotic process involved in the terminal differentiation program of epidermal keratinocytes.
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PMID:Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo. 774 3

We investigated the expression of Fas(CD95) on hematopoietic progenitor cells. CD34+ cells freshly isolated from bone marrow did not express Fas. However, interferon-gamma(IFN-gamma) and/or tumor necrosis factor-alpha (TNF-alpha) induced the expression of Fas after 48 hours of serum-free culture. The TNF-alpha-induced Fas expression is mediated by p55-TNF-alpha receptor. Human CD34+ cells expressed Fas following low dose ionizing radiation in a dose-dependent fashion. CD34+ cells isolated from bone marrow were cultured with hematopoietic growth factors for 7 days. CD34+ cells cultured with hematopoietic growth factors gradually became positive for Fas and rapidly lost Bcl-2 expression. Fas system is considered to play important roles at the level of hematopoietic progenitor cells in both physiologic and pathologic conditions.
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PMID:[Fas antigen expression on human hematopoietic progenitor cells]. 874 68

To find out how physiologically secreted IFN-gamma controls either the proliferation or the apoptosis of human T lymphocytes, the kinetics of expression of the alpha- and beta-chains of its receptor (IFN-gamma R) were sequentially followed on T lymphocytes first activated with PHA and then cultured in the presence of IL-2, and related to the kinetics of expression of Fas, Bcl-2, and IL-2R p55 chain. Both IFN-gamma R chains were poorly expressed on the membrane of resting T lymphocytes. Following their stimulation with PHA, IFN-gamma R alpha but not IFN gamma R beta-chain up-modulated before T lymphocyte entry into the S phase, and then IFN-gamma R alpha down-modulated when they passed through the S and G2/M. The ensuing proliferative response was inhibited by an anti-IFN-gamma R alpha mAb that impeded the binding of IFN-gamma. When PHA-activated T lymphoblasts were cultured for 16 days with IL-2, IFN-gamma R alpha expression increased, whereas that of the beta-chain remained barely detectable. Fas and Bcl-2 were both highly expressed. When these T lymphoblasts were restimulated by PHA, OKT3, or Staphylococcus enterotoxin beta-pokeweed mitogen, both chains up-modulated and most cells underwent apoptosis in a way apparently independent of Bcl-2, but not of Fas. This apoptosis, too, was prevented by the anti-IFN-gamma R alpha mAb. Physiologically secreted IFN-gamma is thus involved in the activation of resting T lymphocytes and in the apoptosis of reactivated lymphoblasts. However, high expression of IFN-gamma R beta took place when IFN-gamma induced apoptosis, but not when it induced proliferation. In conclusion, a correlation exists between differential expression of the IFN-gamma R beta-chain and the delivery by IFN-gamma of proliferative or apoptotic signals.
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PMID:Switching on of the proliferation or apoptosis of activated human T lymphocytes by IFN-gamma is correlated with the differential expression of the alpha- and beta-chains of its receptor. 875 12

Transforming growth factor-beta (TGF-beta) plays a role as an immunosuppressive cytokine within the central nervous system (CNS). The CNS cells targeted by action of TGF-beta1 have not been defined. In this study, we tested the effect of TGF-beta1 on microglia, astrocytes and oligodendrocytes from newborn rats. TGF-beta1 selectively induced apoptosis of microglia, and not of astrocytes or oligodendrocytes. To study the apoptotic mechanism, bcl-2 oncoprotein expression in microglia, astrocytes and oligodendrocytes was measured. Bcl-2 was mainly expressed in microglia, indicating that microglial bcl-2 does not prevent TGF-beta1-mediated microglial apoptosis. The relative protein expression of bcl-2 in microglia was not related to frequency of microglial apoptosis. Thus, TGF-beta1-induced microglial apoptosis was regulated by a bcl-2-independent mechanism. Expression of cytokine (IL-1beta, IL-6, IL-12, IFN-gamma and TNF-alpha) mRNA on microglia was not influenced by treatment with TGF-beta1.
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PMID:Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression. 915 92

Interleukin-10 (IL-10), a cytokine from mouse Th2 cells and macrophage that inhibits IL-2 and IFN-gamma production by Th1 cells, has been reported to stimulate growth and differentiation of B cells activated by CD40 or antigen receptor crosslinking. Our early observation revealed that IL-10 had B cell growth factor (BCGF) activity in human B cells preactivated with SAC or anti-Ig. The responsiveness of the preactivated B cells to IL-10 greatly increased when B cells were activated in the presence of IL-2, whereas IL-10 has no BCGF activity when added at the initiation of activation by SAC. To investigate the dual effects (proliferation and apoptosis) of IL-10 on B cells, the expression of a panel of bcl-2 protoncogene family members, bcl-2, bcl-x, mcl-1, and bax, was analyzed when B cells were activated by SAC. Bcl-xL protein was not expressed in the small resting B cells but was induced by SAC stimulation, reaching its peak at 48 hr. The addition of IL-2 further augmented the Bcl-xL expression with the same kinetics, whereas Bcl-2 and Mcl-1 were expressed by resting B cells and enhanced by SAC stimulation. However, the addition of IL-10 at the initiation of activation down-regulated Bcl-xL, Bcl-2, and Mcl-1 expression. At the same time, B cell proliferation was inhibited and apoptotic cell number increased, suggesting the growth arrest and/or apoptosis of B cells. The apoptosis of SAC-activated B cells by IL-10 was further confirmed by propidium iodide-staining and Annexin V-FITC-staining methods. In contrast, IL-10 failed to down-regulate the Bcl-xL and Bcl-2 expression but rather augmented the expression of Mcl-1 of B cells after preactivation for 48 hr with SAC and IL-2. Under this culture condition, B cells responded to IL-10 to proliferate and differentiate, while IL-2 and IL-10 had an additive or synergistic effect. Taken together, our data suggest that IL-10 acts on the induction stage of Bcl-xL expression and regulates the apoptosis and proliferation of SAC-activated B cells through their bcl-2 family gene expression.
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PMID:The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression. 918 96

The authors were interested to investigate the effect of Cyclosporin A (CsA), known to block interleukin-2 (IL-2) production, or of anti-interferon-gamma antibodies (anti-IFN-gamma Abs) in a model of T cell tolerance induced by the injection of the superantigen Staphylococcal Enterotoxin B (SEB) in BALB/c mice. After SEB immunization, tolerance was mainly achieved through deletion and anergy of SEB-reactive V beta 8+ T cells. Association of CsA treatment with SEB led to a greater decrease of the percentage of V beta 8+ CD4+ lymphocytes in the spleen and an abolition of clonal energy. In contrast, treatment of SEB primed mice with anti-IFN-gamma Abs resulted in an increased percentage of V beta 8+ CD4+ cells without affecting the induction of clonal anergy. The authors found that 1-2 h after SEB priming, splenic mRNA levels of IFN-gamma and IL-4 were decreased by either CsA and anti-IFN-gamma Abs, whereas FasL, Bcl-2, p. 53, and c-myc levels were not influenced by either treatment. However, SEB-induced IL-2 and IL-10 mRNA expression was suppressed only by CsA, whereas tumour necrosis factor-alpha (TNF-alpha) was decreased only by anti-IFN-gamma Abs. To investigate whether the effect of CsA on the tolerance mechanisms was related to suppression of IL-2, CsA was administered together with recombinant IL-2. Whereas anergy was not influenced, the decreased percentage of V beta 8+ CD4+ cells seen in CsA-treated animals in the second week after SEB injection was partially corrected by the administration of IL-2. Experiments involving bromodeoxiuridine incorporation revealed that the latter effect of IL-2 was mainly due to a correction of the defective proliferation of V beta 8+ T cells after SEB injection in CsA-treated mice. These results suggest that the effect of CsA and anti-IFN-gamma Abs on tolerance mechanisms are in part explained by their action on cytokines.
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PMID:Effect of treatments with cyclosporin A and anti-interferon-gamma antibodies on the mechanisms of immune tolerance in staphylococcal enterotoxin B primed mice. 939 28

Fas antigen is constitutively expressed in the normal colon epithelium, but considerably diminished in most colorectal carcinomas. In the present study, we examine the relationship between Fas antigen expression and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had no effect on the induction of apoptosis of COLO 201. However, TNF-alpha and/or IFN-gamma, independently and additively, up-regulated Fas antigen expression on COLO 201 and induced apoptosis in a dose-dependent manner. Both cytokines also increased the COLO 201 sensitivity to anti-Fas antibody, resulting from the down-modulation of Bcl-2 and the up-regulation of Bax. These findings indicate that cytokine(s) plus anti-Fas antibody (which mimics natural Fas ligand) are more effective in inducing apoptosis of COLO 201 than cytokine(s) alone. These findings suggest that immunotherapy in combination with cytokine(s) and lymphokine-activated killer (LAK) cells will become a more effective therapy for cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages.
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PMID:Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma), resulting from down-modulation of Bcl-2 expression. 3192 65

It has been proposed that HIV infection is associated with an imbalance in Th1 and Th2 subsets. Recent reports indicate that Th1 and Th2 effectors differ in their susceptibility to activation-induced apoptosis. To determine whether increased T cell apoptosis in HIV-infected patients contributes to alterations in cytokine synthesis, we performed single-cell analysis of type 1 and type 2 cytokine production by CD4 and CD8 T cells, simultaneously with detection of apoptosis. We demonstrate that a differential alteration in representation of Th1 subsets, rather than commitment of T cells to secrete Th2 cytokines, occurs throughout HIV infection. A significant decrease in the number of IL-2- or TNF-alpha-producing T cells was observed, whereas those producing IFN-gamma remained preserved. Furthermore, there is a gradient of susceptibility to activation-induced apoptosis (IL-2 < IFN-gamma < TNF-alpha) among the different Th1 subsets. This gradient was detected in both CD4 and CD8 subsets, as well as in control donors and HIV-infected patients, in whom the susceptibility to apoptosis of IL-2 and IFN-gamma producers was increased compared with controls. This differential intrinsic apoptosis susceptibility of Th1 effectors was found to be tightly regulated by Bcl-2 expression. In HIV-infected persons, disappearance of IL-2-producing T cells was a good indicator of disease progression and was correlated with the progressive shrinkage of the CD4+ CD45RA+ T cell compartment and a gradual increased susceptibility to activation-induced apoptosis of the IL-2-producing subset. This close relationship between the CD45RA/CD45R0 ratio, the level of type 1 cytokine production, and susceptibility to apoptosis should be considered in HIV-infected patients under antiviral or immune-based therapies.
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PMID:Differential susceptibility to activation-induced apoptosis among peripheral Th1 subsets: correlation with Bcl-2 expression and consequences for AIDS pathogenesis. 953 Dec 75

An important prerequisite for a successful pregnancy is that the maternal immune system does not reject the fetus. Down-regulation of the T helper 1 (TH1) associated cellular immune response could therefore be essential. With flow cytometric techniques, we show on a single cell level that both CD4+ and CD8+ T cells from peripheral blood produce less TH1 cytokines (i.e. IFN-gamma and IL-2) and more TH2 cytokines (i.e. IL-4) during normal human pregnancy and shortly after delivery than during non-pregnancy. The TH1/TH2 cytokine ratio in T cells of women during pregnancy and after delivery was significantly decreased. In contrast the TH1/TH2 ratio was elevated to near normal in women with recurrent spontaneous abortions, indicating a marked shift towards TH1 immunity. Fas antigen (CD95) on T cells was significantly elevated during pregnancy and in the post-delivery phase whereas the intracellular expression of anti-apoptotic protein Bcl-2 remained unchanged. Nevertheless Fas-mediated apoptosis in T cells was markedly reduced during normal human pregnancy. We hypothesize that TH1 cells undergo predominantly Fas-mediated apoptosis during pregnancy as has been shown in some TH2-prone diseases (e.g. SLE, HIV) where an elevated Fas expression on peripheral T cells is observed. This could explain the exacerbated occurrence of TH2-associated diseases in pregnancy.
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PMID:Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. 958 18

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


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