Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolerance of MHC class II alloantigens can be achieved by intravenous injection of semiallogeneic hematopoietic cells into neonatal mice. Lymphoid cells of tolerant mice fail to proliferate or secrete interleukins IL-2 or IL-4 when stimulated in vitro with tolerogen. Since the lymphoid organs of B10.T(6R) tolerant mice contain normal levels of I-E reactive (V beta 11+) CD4+ T cells, deletion of alloreactive T cells does not appear to be the mechanism involved in the tolerance induction. To test whether T cells from tolerant animals can become activated under conditions that do not involve alloantigen stimulation, we stimulated these cells with immobilized anti-V beta 11 antibodies. Spleen cells from grafted tolerant and rejector mice proliferated in response to anti-V beta 11+ antibodies, suggesting they were not inert. We then tested whether V beta 11+ T cells from grafted mice can be induced to proliferate following stimulation with alloantigen in vivo. We adoptively transferred T cells from grafted tolerant and rejector mice into irradiated (B10.AQR x B10.T(6R))F1 mice and harvested the lymphoid organs after 65 h. Cells from both grafted tolerant and rejector mice underwent blast transformation, but only cells from rejector mice proliferated when exposed to immobilized anti-V beta 11 antibodies. The failure of V beta 11+ cells from tolerant mice to proliferate after in vivo stimulation may be because they are apoptotic. To test this hypothesis, spleen cells from naive or neonatally tolerized (with (B10.AQR x B10.T(6R))F1 cells) B10.T(6R) mice were adoptively transferred into irradiated (B10.AQR x B10.T(6R))F1 mice and bcl-2 expression was analysed in harvested V beta 11+ cells. Large cells recovered from recipients of naive 6R cells expressed bcl-2 mRNA. By contrast, large cells harvested from recipients of tolerized 6R cells did not express bcl-2 mRNA, suggesting bcl-2 mRNA expression was downregulated in these mice. Moreover, in another experiment, large V beta 11+ cells from grafted tolerant animals recovered after transfer into irradiated (B10.AQR x B10.T(6R))F1 mice did not express the bcl-2 protein as determined by flow cytometry, and contained fragmented DNA as assessed by the TUNEL method. Taken together, these data suggest that MHC class II tolerant T cells undergo apoptosis upon re-exposure to tolerogen in vivo.
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PMID:MHC class II tolerant T cells undergo apoptosis upon re-exposure to tolerogen in vivo. 876 18

The responses of lymphocytes to IL-2 and IL-12, involving proliferation, differentiation, and cytokine production, are only partially overlapping, and may depend on induced differential expression of specific sets of genes. Using reverse-transcription PCR differential display, we isolated an mRNA species expressed in IL-2- but not IL-12-stimulated NK cells. This was identified as the mRNA encoding the transcription factor egr-1, which is expressed with fast kinetics in T and NK cells upon IL-2, but not IL-12, stimulation. Analysis of the accumulation of mRNA-encoding members of the AP-1 transcription factor family demonstrated that c-fos and junB are also expressed upon stimulation of NK and T cells with IL-2, but not IL-12, whereas expression of c-jun and junD is not modified by either cytokine. Accordingly, increased AP-1 DNA-binding activity and AP-1-dependent transcriptional activity were detected exclusively in IL-2-stimulated cells. Analysis of the expression of genes reported to regulate cytokine-induced proliferation demonstrated that both IL-2 and IL-12 induce c-myc mRNA accumulation in NK and T cells, whereas only IL-2 induces bcl-2 expression. Our data provide the first demonstration that IL-12-mediated activation of T and NK cells does not involve expression of members of the immediate-early activation genes family (egr-1, c-fos, and junB), AP-1 transcriptional activity, or bcl-2 expression. This indicates that functional differences observed in IL-2- and IL-12-stimulated cells may depend, at least in part, on differential gene regulation.
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PMID:IL-12-induced activation of NK and T cells occurs in the absence of immediate-early activation gene expression. 887 17

Interferon-alpha has been used as therapy in patients with B-cell chronic lymphocytic leukaemia (B-CLL), and is able to induce remissions in patients with early stage disease. Although interferon-alpha exhibits a wide variety of cellular effects, none of these have adequately explained the mechanism of action of interferon-alpha in B-CLL. Recent attention has focussed on the role of bcl-2 in B-CLL, and the regulation of bcl-2 expression by cytokines. B-CLL is characterized by the relentless accumulation in the peripheral blood and bone marrow of a monoclonal population of long-lived B-cells. However, when these cells are cultured in vitro, they die rapidly by apoptosis or programmed cell death. It has recently been demonstrated that B-CLL cells can be protected from apoptotic death in vitro by co-culture with cytokines, such as IL-1, IL-2, IL-4, IL-6 and interferon-gamma. The protection against apoptosis is correlated with increased levels of bcl-2 expression. It was suggested that interferon-alpha induced remissions in early stage B-CLL by interrupting these growth-factor dependent survival pathways and allowing the cells to die by apoptotic death in vivo. However, interferon-alpha has also been shown to protect B-CLL cells from apoptotic death in vitro. This suggests that interferon-alpha does not produce remission in B-CLL by direct effects on B-CLL cells in the circulation. Many of the cytokines which protect B-CLL cells from apoptotic cell death, are members of the cytokine receptor family which utilize a common family of signal transduction molecules. Further elucidation of these signal transduction pathways may offer the prospect of developing novel therapeutic strategies aimed at inducing apoptosis of the malignant clone in vivo.
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PMID:Interferon-alpha, Bcl-2 expression and apoptosis in B-cell chronic lymphocytic leukemia. 890 68

Certain cytokines are involved in the generation of natural killer (NK) cells and participate in the regulation of the proto-oncogene bcl-2. We aimed to study the mRNA expression of interleukin (IL)-2, IL-4 and IL-5, the composition of the tumour infiltrating lymphocytes (TIL), and the expression of bcl-2 in 14 benign and malignant human parotid tumours. T IL were predominantly composed of T lymphocytes and NK cells. We found evidence for the homing of T cells, and for generation of NK cells in the vicinity of the tumours. mRNA for IL-2 and IL-12, were identified but IL-4 mRNA was not found. The cytokine profiles and the composition of TIL of the two tumour categories were indistinguishable, suggesting that these host-response variables do not explain the differences in biological behaviour of these particular tumours. The results support a shift towards Th 1 (T helper 1) cells and interferon-gamma production, and that IL-12 also in vivo may play an important role in the regulatory interaction between innate resistance and adaptive immunity in tumour diseases. Most infiltrating lymphocytes showed strong expression of bcl-2; an interesting observation with regard to lymphocytic apoptosis in neoplastic diseases. The immunoreactivity for the bcl-2 protein varied considerably between and within tumours, and almost all benign tumours showed strong bcl-2 positively whereas several of the malignant tumours showed weak or absent staining. The variable expression of bcl-2 protein suggests a different susceptibility of tumour cells to apoptosis. The results also indicate that bcl-2 cannot pla a major role as protective agent in the specific apoptotic pathway induced by NK cells.
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PMID:Bcl-2 immunoreactivity in salivary gland neoplasms is unrelated to the expression of mRNA for natural killer cell stimulatory cytokines interleukin (IL)-2 and IL-12. 891 16

Tyrosine kinases (TK) and G proteins act as second, messengers for intracellular signal transduction. TK activates the cascade of protein phosphorylation. G proteins are heterodimer complex with alpha, beta, and gamma subunits. PLC activated by GTP-binding alpha subunit lyses membrane phosphatidyl inositol (PI), releasing diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 releases calcium into cytoplasm to activate calcineurin, causing a NF-AT cytoplasmic factor (NF-ATc) to translocate to nucleus. DAG activates protein kinase C (PKC), which synthesizes another nuclear factor NF-ATn. When NF-ATc and NF-ATn assemble to form the complex on the promoter site of DNA, transcription of IL-2 mRNA begins. PKC also induces phosphorylation of I-kappa B to release NF-kappa B. The complex of CsA or FK506 with CyP or FKBP, respectively, inhibits the activation of calcineurin. FKBP-binding rapamycin inhibits cell proliferation and differentiation by inactivation of p70 s6 kinase. RS61443 and mizoribine influence specifically on the de novo pathway of purine biosynthesis. DSG may bind to Hsc 70 and inhibit the translocation of NF-kappa B into nucleus. FTY720 induces lymphocyte-specific apoptosis, independently on Fas-antigen expressions. by modulating bcl-2 genes.
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PMID:[Transplantation immunology and immunosuppressive drug]. 901 Aug 51

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.
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PMID:Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. 902 22

Chronic lymphoproliferative disorders are a heterogeneous group of diseases with a highly variable clinical course. In the past few years, important progress has been made in the classification, biology, and therapy of some of these disorders of which B-cell chronic lymphocytic leukemia is not only the most frequent but also the model for their study. Regarding classification, entities that may be confounded with chronic lymphocytic leukemia have been identified (eg, splenic lymphoma with villous lymphocytes, mantle-cell lymphoma in leukemic phase); these diseases should be known and clearly separated from chronic lymphocytic leukemia because their prognosis and treatment is different from that of chronic lymphocytic leukemia. On the other hand, the molecular basis of some of these diseases (eg, the overexpression of the Prad1/CCND1 gene in mantle-cell lymphomas, the relationship between bcl-2 and bax expression in chronic lymphocytic leukemia homeostasis, the role of p53 tumor suppressor gene mutations in chronic lymphocytic leukemia progression) are increasingly well known. Cytokines (eg, tumor necrosis factor-alpha or IL-2, IL-4, and IL-13) also contribute to the pathogenesis of lymphoproliferative disorders by either promoting cell growth or inhibiting apoptosis. In addition, new treatment possibilities (eg, purine analogues, hemopoietic progenitors transplants) are changing the treatment objectives in some of these diseases. Thus, symptoms' palliation is no longer the only realistic aim in the management of patients with chronic lymphoproliferative disorders, but sustained complete remissions and even cures can be achieved.
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PMID:Chronic lymphoproliferative disorders. 909 Apr 92

c-Myb, the cellular homologue of the transforming gene of the avian myeloblastosis virus, is preferentially expressed in all hematopoietic lineages, including T and B lymphocyte lineages. In T lymphocytes, c-Myb expression appears to be required for cell cycle progression and proliferation. To further investigate the role of c-Myb in T cell proliferation and survival, interleukin (IL) 2-dependent CTLL-2 cells were transfected with a constitutively active c-myb or with a c-myb antisense construct able to down-regulate endogenous Myb levels, and the transfectants were assessed for proliferation and survival in low concentrations of IL-2 and for susceptibility to dexamethasone-induced apoptosis. Compared with control cells, CTLL-2 cells constitutively expressing c-Myb proliferate in low concentrations of IL-2 and are less susceptible to apoptosis induced by IL-2 deprivation or treatment with dexamethasone. In contrast, cells transfected with an antisense c-myb construct do not proliferate in low concentrations of IL-2 and undergo apoptosis upon IL-2 deprivation or dexamethasone treatment more rapidly than parental cells. Overexpression of c-Myb was accompanied by up-regulation of BCL-2 expression. In transient transfection assays, the murine bcl-2 promoter was efficiently transactivated by c-Myb, but such effect was observed also in cells transfected with a DNA binding-deficient c-myb construct. Moreover, in gel retardation assays, a 38-bp oligomer in the shortest bcl-2 promoter segment regulated by c-Myb formed a specific complex with nuclear extracts from c-Myb-transfected CTLL-2 cells. Thus, these results strongly suggest that c-Myb, in addition to regulating T cell proliferation, protects T lymphocytes from apoptosis by induction of BCL-2 expression, which involves a c-Myb-dependent mechanism of promoter regulation.
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PMID:Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation of bcl-2 promoter activity. 909 87

Leukaemic CD5+ B cells obtained from B cell chronic lymphocytic leukaemia (B-CLL) patients rapidly undergo apoptosis during in vitro culture. This is associated with down-regulation in expression of bcl-2. Spontaneous apoptosis of these cells contrasts their enhanced longevity in vivo and suggests that apoptosis-inhibitory factors may be responsible for the accumulation of leukaemic cells in B-CLL. The effect of different cytokines on apoptosis and bcl-2 expression was examined in six populations of leukaemic CD5+ B cells. Consistent with previous data, IL-4 and IFN-gamma suppressed apoptosis in 6/6 and 5/6 cell populations, respectively. Interestingly, the ability to suppress apoptosis in leukaemic CD5+ B cells was also found to be a property of IL-2, IL-6, IL-13 and TNF-alpha. In the presence of these cytokines, 10-40% more viable cells were detected, compared with unstimulated cultures. Enhancement of cell viability and suppression of apoptosis were associated with a delay in down-regulation of bcl-2. These results suggest a role for autocrine and paracrine growth factors in the pathogenesis of B-CLL, and indicate that cytokines which prevent apoptosis in vitro may be targets for treating this malignancy.
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PMID:Human cytokines suppress apoptosis of leukaemic CD5+ B cells and preserve expression of bcl-2. 910 64

AK-5 tumor cell death is mediated by natural killer cells through necrosis (perforin mediated) and apoptosis. Apoptosis is the mechanism which operates in immune animals in vivo. We have identified natural killer (NK) cell as the effector cell which induces apoptosis leading to tumor cell death in vivo. Naive NK cell which is unable to kill the AK-5 tumor cell can be activated with IL-2/IL-12 to make it capable of inducing apoptosis in tumor cells. NK cells from tumor-rejected animals show higher expression of Fas ligand and serine esterase granzyme B. In addition, NK cell-mediated apoptosis in AK-5 cells is totally abolished when effector cells are treated with anti-NKR-P1 mAb 3.2.3 and complement. NK cell-mediated apoptotic activity is inhibited in bcl-2 transfected tumor cells; however, the cytotoxic activity (perforin-mediated) remains unaffected. These observations suggest an important role for activated NK cells in inducing tumor cell death through necrosis (ADCC) and apoptosis leading to spontaneous regression of the AK-5 tumor in syngeneic animals.
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PMID:Natural killer cell as the effector which mediates in vivo apoptosis in AK-5 tumor cells. 914 99


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