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)

We have shown that the ability of the human follicular lymphoma-derived cell line SU-DHL-6 to proliferate and survive in vitro depends on both Bcl-2 expression and multiple autocrine growth factors. Treatment with Bcl-2 antisense (AS Bcl-2) decreased Bcl-2 protein levels. However, a cytotoxic effect was seen only at very restricted cell densities. Below such densities cells underwent spontaneous death without any treatment, while above these cell densities no cytotoxic effect of AS Bcl-2 could be seen. The conditioned medium of SU-DHL cells supported the survival and growth of these cells cultivated at low cell densities and partially reversed the cytotoxicity associated with Bcl-2 depletion. RT/PCR analysis revealed autocrine expression of IL-1 beta, IL-2, IL-5 and TNF-beta in SU-DHL cells. Neutralizing antibodies against these cytokines inhibited SU-DHL proliferation. Thus, development of autocrine GF secretion may be the second step in the pathogenesis of follicular lymphomas.
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PMID:The role of Bcl-2 protein and autocrine growth factors in a human follicular lymphoma-derived B cell line. 779 71

Recent studies of transgenic mice have confirmed that clonal deletion is involved in the development of B cells. However, little is known about intercellular and intracellular molecular events regulating B cell clonal deletion. We investigated the role of bcl-2 and cytokines in the regulation of B cell clonal deletion using anti-IgM-induced growth arrest and apoptosis in immature B cell lines as a model. We show here that overexpression of Bcl-2 protein in stably transfected immature B cells partially inhibits anti-Ig M-induced apoptosis but does not affect growth arrest. Similarly, IL-5 has a strong inhibitory effect on anti-IgM-mediated apoptosis but has a weak inhibitory effect on growth arrest. Finally, although both bcl-2 overexpression and exogenous IL-5 cooperate with bacterial LPS to block apoptosis, bcl-2 overexpression and exogenous IL-5 have no additive inhibitory effect on anti-Ig induced apoptosis. These findings indicate that anti-IgM-induced apoptosis is independently regulated from growth arrest and is controlled by at least two independent pathways: One is regulated by either Bcl-2 protein or IL-5 and the other is regulated by LPS. Activation of both the bcl-2/IL-5 and LPS pathways is necessary for complete inhibition of apoptosis, and presumably, clonal selection of the immature B cells.
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PMID:Role of bcl-2 and IL-5 in the regulation of anti-IgM-induced growth arrest and apoptosis in immature B cell lines. A cooperative regulation model for B cell clonal deletion. 814 16

Accelerated apoptosis and improper expression of cytokine genes have been considered as important defects of lymphocytes for the development of systemic lupus erythematosus (SLE). This study was undertaken to test the possible contribution of serum factors obtained from SLE patients to these abnormalities. Molt-4 and Jurkat cells constantly exhibited a slower growth rate as well as more dead cells in culture with SLE sera tested than controls, although the cell cycle progression was apparently unaffected. Increased apoptosis was demonstrable among SLE sera-cultured cells by ELISA for apoptosis-specific DNA fragments and terminal deoxynucleotidyl transferase (TdT) in situ death analysis. Different levels of Fas, Fas-L, and Bcl-2 gene products were not detected between SLE sera-treated cells and the controls. The transcripts of interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) genes of these two T cell lines were evidently increased in the presence of SLE sera, while IL-2 and IL-4 were unaffected. Elevated expression of IL-5 was also found in Molt-4 cells. By contrast, SLE sera reduced the transcripts of IL-6 gene in Jurkat cells. The effects of SLE sera were independent of corticosteroid medication. These results suggest that serum abnormalities may also play a role in T cell dysfunction.
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PMID:Induction of apoptosis and cytokine gene expression in T-cell lines by sera of patients with systemic lupus erythematosus. 901 May 6

The expression of the Bcl-2 family proteins Bax, Mcl-1, Bcl-2, and Bcl-xL, was examined in human peripheral blood eosinophils or in umbilical-cord-blood-derived eosinophils. Immunoblot analysis disclosed high amounts of the proapoptotic factor Bax in freshly purified eosinophils of both types. Although cord-blood-derived eosinophils expressed easily detectable levels of Mcl-1, Bcl-2, and Bcl-xL, only traces or no expression of these three antiapoptotic proteins were found in peripheral blood eosinophils. Incubation of both eosinophil types for 1 to 3 days in a cytokine-deprived medium led to apoptosis, without changes in the expression of Bax, Mcl-1, Bcl-2, or Bcl-xL. Although addition of interleukin-5 or interferon-gamma (IFN-gamma) to the culture medium increased the survival of both eosinophil types, a rise in the levels of Mcl-1 was observed only in IFN-gamma-treated cord-blood eosinophils. Together, these results indicate that human eosinophils have a specific profile of Bcl-2-family protein expression that depends on their maturation status and may be modulated by stimuli that influence their survival.
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PMID:Human eosinophils express bcl-2 family proteins: modulation of Mcl-1 expression by IFN-gamma. 949 Jun 49

Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils.
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PMID:Role for Bcl-xL in delayed eosinophil apoptosis mediated by granulocyte-macrophage colony-stimulating factor and interleukin-5. 968 Mar 44

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1-like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon gamma (IFN-gamma) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-gamma production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-gamma-deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2(lck) transgenic mice were poorly protected by IL-12, whereas IL-10-deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-gamma, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.
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PMID:Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. 989 5

The Bcl-2 family has been shown to be vital regulators of programmed cell death in numerous systems. To investigate the role of such proteins in the regulation of apoptosis of eosinophils, the expression of Bcl-2 and homologues Bcl-xL (death antagonists), Bax, and Bcl-xS (death agonists) were examined by immunoblot, flow cytometry, and reverse transcriptase-polymerase chain reaction analysis. Potential modulation of apoptosis-associated molecules during spontaneous apoptosis and in the presence of interleukin (IL)-5 was also investigated. Peripheral blood eosinophils were found to express constitutively Bax and Bcl-x, but Bcl-2 was absent. Analysis of mRNA revealed that the bcl-xL isoform predominated, although bcl-xS was also detectable. Spontaneous apoptosis due to culturing in the absence of cytokines for 24 h did not result in modulation of any of the Bcl-2 homologues examined. Culturing eosinophils in the presence of 100 pg/ml IL-5 for 24 h significantly reduced apoptosis (P < 0.01) to 10.7 +/- 2.6% compared with 46.8 +/- 7.4% in the absence of IL-5, and induced Bcl-2 mRNA and protein expression, with no detectable change in Bax, Bcl-x, or beta-actin as a control. This investigation indicates a specific profile of apoptotic molecules in eosinophils distinct from that of neutrophils, and indicates that survival-enhancing IL-5 modulates the expression of Bcl-2 in vitro.
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PMID:Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5. 1010 Oct 4

In vitro proliferation of hematopoietic stem cells requires costimulation by multiple regulatory factors whereas expansion of lineage-committed progenitor cells generated by stem cells usually requires only a single factor. The distinct requirement of factors for proliferation coincides with the differential temporal expression of the subunits of cytokine receptors during early stem cell differentiation. In this study, we explored the underlying mechanism of the requirement of costimulation in a hematopoietic progenitor cell line TF-1. We found that granulocyte-macrophage colony-stimulating factor (GM-CSF) optimally activated proliferation of TF-1 cells regardless of the presence or absence of stem cell factor (SCF). However, interleukin-5 (IL-5) alone sustained survival of TF-1 cells and required costimulation of SCF for optimal proliferation. The synergistic effect of SCF was partly due to its anti-apoptosis activity. Overexpression of the IL-5 receptor alpha subunit (IL5Ralpha) in TF-1 cells by genetic selection or retroviral infection also resumed optimal proliferation due to correction of the defect in apoptosis suppression. Exogenous expression of an oncogenic anti-apoptosis protein, Bcl-2, conferred on TF-1 cells an IL-5-dependent phenotype. In summary, our data suggested SCF costimulation is only necessary when the expression level of IL5Ralpha is low and apoptosis suppression is defective in the signal transduction of IL-5. Expression of Bcl-2 proteins released the growth restriction of the progenitor cells and may be implicated in leukemia formation.
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PMID:Optimal proliferation of a hematopoietic progenitor cell line requires either costimulation with stem cell factor or increase of receptor expression that can be replaced by overexpression of Bcl-2. 1019 36

IL-5 is a potent eosinophil viability-enhancing factor that has been strongly implicated in the pathogenesis of IgE-mediated inflammation in vivo. Recently published data have suggested that IL-5 (and related cytokines) may act by altering the expression of the anti-apoptotic regulator Bcl-2 or its homologues, but this is controversial. The behaviour of the recently described pro-apoptotic cysteine proteases (caspases) in eosinophils after IL-5 treatment has not been explored. We examined the effect of IL-5 on the expression of four major Bcl-2 homologues, as well as on the expression/activation of key members of the caspase cell death cascade in cultured circulating human eosinophils. The effect of relevant inducers of eosinophil apoptosis (glucocorticoid and Fas ligation) on these regulatory proteins was also examined. We observed baseline expression of the anti-apoptotic Mcl-1 and pro-apoptotic Bax proteins in immunoblots of eosinophil lysates, but not Bcl-x, Bcl-2. IL-5 treatment had the effect of maintaining this basal level of expression over time without altering the balance of Bcl-2 homologues. The (upstream) caspase 8 and (downstream) caspase 3 proenzymes were detected in eosinophils at baseline, and were processed during spontaneous and stimulated eosinophil death. IL-5 completely blocked caspase processing in spontaneous and dexamethasone-induced cell death, and significantly slowed processing during Fas ligation. Our data do not support the theory that IL-5 acts by altering the balance of anti-apoptotic and pro-apoptotic Bcl-2 homologues, but suggest that it may act by regulating activation of the caspase cell death cascade.
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PMID:Effect of IL-5, glucocorticoid, and Fas ligation on Bcl-2 homologue expression and caspase activation in circulating human eosinophils. 1075 58

Stem cell factor (SCF) has been suggested as essential for optimal production of various hematopoietic lineages mainly because of its apoptosis prevention function when it costimulates with other cytokines. However, the underlying mechanism of this synergism of apoptosis prevention is largely unknown. The present study examined the expression of some Bcl-2 family members, including Bcl-2, Bcl-X(L), Mcl-1, and Bax, in response to cytokine stimulation in TF-1 and JYTF-1 cells in which SCF costimulation is differentially required for optimal proliferation. The results revealed that only the expression of Mcl-1 highly correlated with the antiapoptotic activity of interleukin-5 (IL-5) and the synergistic effect of SCF. In TF-1 cells, the defect of IL-5 in apoptosis suppression and Mcl-1 induction was associated with the incapability to highly phosphorylate Janus kinases (JAK1, JAK2), signal transducer and activator of transcription-5 (STAT5), mitogen-activated protein kinase (MAPK), and Akt/PKB, whereas SCF costimulation restored the potent phosphorylation of MAPK and Akt/PKB, but not STAT5. The importance of MAPK and Akt/PKB signaling pathways in regulating the expression of Mcl-1 and cell survival was further supported by the observation that inhibition of MEK by PD98059 or phosphatidylinositol-3 kinase (PI-3K) by LY294002 independently resulted in the reduction of Mcl-1 expression and loss of cell viability. Therefore, the data suggest that Mcl-1 is a common antiapoptotic target of both early-stage cytokine SCF and late-stage cytokine IL-5. Both MEK/MAPK and PI-3K/Akt signaling pathways are essential in the regulation of Mcl-1 expression and apoptosis prevention. (Blood. 2000;96:1764-1771)
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PMID:Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways. 1096 75


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