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)

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

We recently showed that mature T lymphocytes derived from elderly humans were more susceptible to activation-induced cell death than similar cells from young individuals. Because this excessive apoptosis is unrelated to either the age-associated decrease in IL-2 production, a differential Bcl-2 expression or to a modification of the antioxidant pathway, we examined the possibility that the Fas receptor (FasR) is directly implicated in the generation of the unwarranted death signal. We investigated the expression and the function of FasR on T lymphocyte populations from healthy young and elderly individuals. We found that the frequency of FasR+ T cells increases as a function of age. The FasR expressed at the surface of freshly isolated T lymphocytes from elderly donors appear to be fully functional since their ligation by a cytocidal IgM anti-Fas mAb leads to a significant increase in DNA fragmentation in this cell population. Conversely, exposure of T cells derived from aged individuals to an antagonistic anti-FasR mAb partially prevents the age-related increase in apoptotic cell death. The population of FasR+ T lymphocytes is essentially constituted of previously activated CD45RO+ cells and also includes recently activated lymphocytes bearing the CD25 and CD69 activation markers. The accumulation of chronically and recently in vivo activated T-cells with age probably contributes to the amplification of the process of Fas-mediated cell death in T lymphocytes isolated from senescent organisms.
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PMID:Susceptibility to apoptosis of T lymphocytes from elderly humans is associated with increased in vivo expression of functional Fas receptors. 922 9

We have previously demonstrated that CD4 cross-linking (CD4XL) results in apoptosis of CD4+ T cells and augmentation of Fas antigen (CD95, APO-1) expression in CD4+ and CD8+ T cells. Here we demonstrate that CD4XL mediated by both, anti-CD4 monoclonal antibody (MoAb) or human immunodeficiency virus (HIV) envelope protein gp120 reduces the expression of the proto-oncogene Bcl-2 in CD4+ T cells, but not in CD8+ T cells, concurrently with the induction of CD4+ T cell-apoptosis. Additionally, the Bcl-2dim population expressed high levels of Fas antigen. Bax, an antagonist of Bcl-2, was brightly expressed even in the Bcl-2dim population. Addition of interleukin (IL)-2 rescued CD4+ T cells from CD4XL-induced Bcl-2 downmodulation and apoptosis induction. These results support the hypothesis that CD4 ligation by HIV-1 envelope protein in vivo in HIV-infected patients selectively reduces Bcl-2 protein in CD4+ T lymphocytes, thereby facilitating Fas/Fas-ligand triggered apoptosis; furthermore the findings reported expand the rationale for use of IL-2 in HIV disease.
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PMID:Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2. 922 75

Lymphokine-dependent cells undergo apoptosis upon lymphokine withdrawal. We describe that lymphokine deprivation of the interleukin (IL)-2- or IL-4-dependent mouse T cell line TS1 alpha beta induces Ras activation which plays a role in programmed cell death, since blocking Ras activity reduces the induction of apoptosis. Induction of apoptosis by lymphokine deprivation can be prevented by expression of the Bcl-2 protein. Rescue from cell death by IL-2 also promotes Ras activation, but, in contrast to lymphokine withdrawal, stimulates Bcl-2 expression. IL-4-induced cell survival is Ras- and Bcl-2 independent. These results are compatible with a model in which cell proliferation requires the simultaneous induction of at least two pathways which act in combination to prevent cell death.
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PMID:Ras activation leads to cell proliferation or apoptotic cell death upon interleukin-2 stimulation or lymphokine deprivation, respectively. 924 68

Homeostasis of human B cell development is maintained by a complex network of cytoplasmic and surface expressed molecules. Abnormalities in this process may result in the expansion of malignant B cell precursors in B lineage acute lymphoblastic leukaemia (ALL). ALL cells share surface antigens with normal early precursor B cells. We have studied here the role of Fas/APO-1 (CD95) antigen on leukaemic precursor B cell line growth and survival, and the modulation of its effects by signals involved in normal early B cell development. Four ALL cell lines representative of the early steps of B cell differentiation are shown to express surface Fas/APO-1 (CD95) antigen and to undergo apoptosis in the presence of anti-Fas cross-linking antibodies. This effect is strongly enhanced when pre-B, but not pro-B cells, are pretreated with IL-7 but not with IL-2, IL-3, IL-4 or IL-10. Furthermore, pre-B cell death induced by anti-Fas antibodies in combination with IL-7 is increased upon pre-B receptor but not CD19 cross-linking. Bcl-2 and Bax protein expression is not influenced by IL-7 or pre-BR stimulation in either pro-B or pre-B cell lines. These results indicate that signals involved in normal early B cell development can modulate the Fas (CD95)-mediated apoptosis of leukaemic precursor B cells.
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PMID:IL-7 sensitizes human pre-B cells but not pro-B cells to Fas/APO-1 (CD95)-mediated apoptosis. 936 21

We demonstrate that interleukin-10 (IL-10) can inhibit T-cell apoptosis. T cells, within a PBMC (peripheral blood mononuclear cell) population, were stimulated via the T-cell receptor and grown in the presence of IL-2. These cells had less apoptosis when in the continuous presence of IL-10, compared with cells grown in the absence of IL-10. Conversely, when stimulated and grown in the presence of neutralizing antibody of IL-10, there was an increase in T-cell apoptosis. The in vitro rescue from apoptotic cell death of other lymphoid cells, such as germinal centre B cells, has been shown by others to involve a Bcl-2 pathway. We therefore investigated whether IL-10 might affect the Bcl-2 expression on cultured T cells. By Western blotting we demonstrated that continuous exposure of IL-10 to T cells (within a PBMC population) enhanced the expression of Bcl-2. Furthermore, T cells protected from apoptotic cell death by IL-10 were indistinguishable from viable untreated cells in their ability to proliferate to either immobilized anti-CD3 or IL-2. Thus, we have shown that continuous culture of T cells in the presence of IL-10 will inhibit T-cell apoptosis because of, at least in part, the upregulation of Bcl-2, and this is associated with a normal proliferative function.
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PMID:Interleukin-10 rescues T cells from apoptotic cell death: association with an upregulation of Bcl-2. 937 Sep 16

Here we describe a Rho-mediated apoptosis suppression pathway driven by Bcl-2 expression in the interleukin (IL)-4- or IL-2-dependent murine T cell line TS1 alpha beta. IL-2, but not IL-4, induces Bcl-2 expression through RhoA activation which is inhibited by the specific Rho family inhibitor, Clostridium difficile Toxin B, as well as by a dominant negative RhoA mutant. Using transient transfections of RhoA mutants tagged with the vesicular stomatitis virus glycoprotein, we show that a constitutively active RhoA mutant induces Bcl-2 expression and prevents apoptosis upon IL-4 withdrawal. Finally, we have identified the signaling pathway involved together with RhoA in Bcl-2 induction and show compelling evidence for the implication of phosphatidylinositol 3 kinase and protein kinase C.
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PMID:Rho prevents apoptosis through Bcl-2 expression: implications for interleukin-2 receptor signal transduction. 939 1

Several cytokines including stem cell factor (SCF) and interleukin (IL)-7 are known to be required for development of gamma delta T cell receptor (TCR) intestinal intraepithelial lymphocytes (i-IEL) in mice. We show here the effects of IL-15 on the proliferation and maintenance of murine gamma delta i-IEL in vitro. gamma delta i-IEL constitutively expressed a high level of IL-15 receptor alpha mRNA and proliferated in response to IL-15 more vigorously than alpha beta i-IEL. V gamma/delta repertoire analysis revealed that IL-15, like IL-2, induced polyclonal expansion of gamma delta i-IEL, whereas gamma delta i-IEL responding to IL-7 showed a V gamma/delta repertoire skewed towards V gamma 1/V delta 4, V delta 5. IL-15 efficiently prevented gamma delta i-IEL from apoptosis induced by growth factor deprivation. This rescue was accompanied by up-regulation of Bcl-2 expression. These results suggest that IL-15 plays important roles in proliferation and maintenance of gamma delta i-IEL.
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PMID:Interleukin-15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing gamma delta T cell receptor in mice. 939 14

Memory T cells are considered to be less dependent on costimulation and to respond more vigorously to TCR triggering compared to their naive counterparts. We and others, however, observed that memory CD4 T cells display nonresponsiveness to a variety of stimuli, including superantigens and soluble anti-CD3. We now report that CD28-derived costimulation can revert the nonresponsive state of antigen-exposed CD4 T cells. Interestingly, the rescuing effect of CD28 can be completely negated by CTLA-4 engagement. The malfunction of memory T cells is related to increased cell death; the viability can be restored by CD28 engagement and is negatively regulated by CTLA-4 engagement. Importantly, it has been reported that antigen-exposed T cells express lower levels of the anti-apoptotic mediator Bcl-2. In addition, CD28 costimulation was reported to upregulate the expression levels of Bcl-xL. We therefore examined the possible role of Bcl-2 family proteins in the nonresponsiveness of antigen-exposed CD4 T cells, and determined whether CTLA-4, in analogy to CD28, mediates its negative regulatory effects via the Bcl-2 family of apoptotic mediators. Our data indicate that neither the nonresponsiveness nor the susceptibility to CTLA-4 of antigen-experienced CD4 T cells are related to the expression levels of Bcl-2 or Bax. The rescuing effects of CD28, however, may be related to increased Bcl-xL levels. Addition of IL-2 normalizes the nonresponsiveness of memory CD4 T cells and renders these cells resistant to the negative effects of CTLA-4 engagement. Impaired IL-2 production is therefore likely to be the cause of the malfunction and CTLA-4 susceptibility of memory CD4 T cells.
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PMID:Nonresponsiveness and susceptibility to CTLA-4 of antigen-exposed CD4 T cells are not regulated by the Bcl-2 family of apoptotic mediators, but can be restored by IL-2. 949 88

We examined the CD8+ T cell response to lymphocytic choriomeningitis virus (LCMV) in mice doubly transgenic for an LCMV-specific TCR and for either bcl-xL or bcl-2. Clonal down-sizing of the anti-viral CD8+ T cell response and the generation of T cell memory was not influenced by constitutive expression of these anti-apoptotic proteins in T cells. Expression of Bcl-xL or Bcl-2 did, however, prevent LCMV peptide-induced peripheral deletion of mature CD8+ T cells in vivo and apoptosis of activated LCMV-specific effector T cells in vitro. The CD8+ T cells "rescued" by Bcl-xL or Bcl-2 from peptide antigen-induced cell death were anergic and this could not be reversed by addition of IL-2 in vitro or by adoptive transfer into antigen-free recipient mice followed by LCMV infection in vivo. Taken together, we show here that 1) Bcl-xL or Bcl-2 are functionally equivalent in their ability to modulate CD8+ T cell survival in vivo, 2) distinct apoptosis signaling pathways exist in CD8+ T cells, one that can be inhibited by Bcl-2 or Bcl-xL and one that cannot be blocked, and 3) apoptosis of CD8+ effector T cells during the declining phase of an immune response is not prevented by constitutive expression of the anti-apoptotic proteins Bcl-xL and Bcl-2.
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PMID:Constitutive expression of Bcl-xL or Bcl-2 prevents peptide antigen-induced T cell deletion but does not influence T cell homeostasis after a viral infection. 952 Oct 66


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