Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both T cells and natural killer (NK) cells express CD2, the target of an alternative activation pathway that induces the proliferation of both cell types. The mitogenic response to CD2 ligation requires the co-expression of CD3:TCR in T cells and FcgammaRIII in NK cells, suggesting that these receptors are involved in transducing the response initiated by CD2. The ability of FcgammaRIII to trigger the activation-induced death of IL-2-primed NK cells led us to investigate the potential for CD2 to trigger activation-induced NK cell death. Our results reveal that the same anti-CD2 monoclonal antibodies (mAb) that activate freshly isolated NK cells induce apoptosis in IL-2-primed NK cells. CD2-induced apoptosis results in chromatin condensation, DNA fragmentation and cleavage of caspase-3. Activation-induced NK cell death triggered by CD2 ligation is extremely rapid (DNA fragmentation is first observed at 90 min) and it is not inhibited by neutralizing antibodies reactive with TNF-alpha or Fas ligand. Whereas mAb reactive with distinct CD2 epitopes (i.e. T11.1, T11.2, and T11.3) are required for activation-induced T cell death, mAb reactive with a single CD2 epitope are sufficient for activation-induced NK cell death. The ability of CD2, CD16, and CD94 to induce apoptosis in IL-2-primed lymphocytes suggests that cytokine priming changes the response to a signaling cascade that is common to each of these activation receptors.
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PMID:Activation-induced NK cell death triggered by CD2 stimulation. 956 69

We have reported that human autoantibodies reacting with the polymorphonuclear neutrophil (PMN)-anchored FcgammaRIIIb (CD16) protect these cells from spontaneous apoptosis. In this study, we used anti-CD16 F(ab')(2) to delineate the mechanism(s) whereby the PMN life span is extended. As documented using four methods, CD16 cross-linking impeded spontaneous apoptosis, whereas anti-CD18 F(ab')(2) exerted no effect. Incubation of PMNs with anti-CD16 prevented the up-regulation of beta(2) integrins, particularly CD11b, which is the alpha-chain of complement receptor type 3, but also CD18, which is its beta-chain, as well as CD11a and CD11c. Anti-CD16-conditioned supernatant of PMNs diminished the percentage of annexin V-binding fresh PMNs after another 18 h in culture, whereas the negative control anti-CD18 had no effect. The expression of mRNA for G-CSF and GM-CSF was induced by anti-CD16, followed by the release of G-CSF and GM-CSF in a dose-dependent manner. Anti-G-CSF and anti-GM-CSF mAbs abrogated the antiapoptotic effect of the related growth factors. The delay in apoptosis was accompanied by a down-regulated expression of Bax, and a partial reduction of caspase-3 activity. These data suggest an autocrine involvement of anti-CD16-induced survival factors in the rescue of PMNs from spontaneous apoptosis. Thus, apoptosis of aged PMNs can be modulated by signaling through FcgammaRIIIb, which may occur in patients with PMN-binding anti-FcgammaRIIIb autoantibodies.
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PMID:Cross-linking of human FcgammaRIIIb induces the production of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by polymorphonuclear neutrophils. 1156 19

Healthy donors infused with high doses of glucocorticoids [GCs; methyl-prednisolone (MP); 500 mg/day for 3 days] suffer a selective depletion of the CD14(+)CD16(+) monocytes such that these cells are reduced by 95% on day 5. In vitro studies revealed that at 11 h of culture in the presence of 10(-)(5) M MP, no depletion was observed as yet, but a reduction by 80% was seen after 24 h. In dose-response analysis, MP still led to a 50% reduction of CD14(+)CD16(+) monocytes at 10(-)(7) M. Depletion could not be overcome by addition of the cytokines interleukin-1beta or macrophage-colony stimulating factor, and it was independent of CD95. Depletion was, however, inhibited by the caspase 3,8 blocker z-Val-Ala-Asp, suggesting that cell death occurs in a caspase-dependent manner. Furthermore, blockade of depletion by RU-486 indicates that the intracellular GC receptor (GCR) is involved. Measurement of GCR by flow cytometry revealed a 50% higher level of expression in the CD14(+)CD16(+) monocytes. Our studies show a selective depletion of CD14(+)CD16(+) monocytes by GC treatment in vivo and in vitro, an effect to which the modestly increased level of GCR may contribute.
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PMID:Mechanism of glucocorticoid-induced depletion of human CD14+CD16+ monocytes. 1283 40

Glomerulonephritis may be triggered by antibody deposits that activate macrophages to promote tissue damage. Macrophage-induced apoptosis of human vascular smooth muscle cells and rodent mesangial cells is potentially relevant to glomerulonephritis. Therefore, studies of macrophage-induced apoptosis were extended to antibody-activated macrophages. That is, we studied antibody dependent cellular cytotoxicity (ADCC). To corroborate results, we studied biochemical versus microscopic measurements, soluble or immobilized immunoglobulin and vascular smooth muscle cells (VSMCs) or mesangial cells (MCs). U937 macrophages and human peripheral blood macrophages provoked antibody-dependent killing of MCs and VSMCs. Macrophage-induced death was apoptotic based on electron microscopy, annexin-V, activated caspase-3 and hypodiploid DNA. ADCC was inhibited by antagonistic antibodies to Fas-L and to CD16 (Fc-gamma-RIII) but not to CD64 (Fc-gamma-RI). In conclusion, antibody-dependent killing of human MCs by human macrophages was via Fas-L and CD16.
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PMID:Human macrophages kill human mesangial cells by Fas-L-induced apoptosis when triggered by antibody via CD16. 1532 Sep 2

SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM.
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PMID:Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. 1635 83

The functionality of polymorphonuclear leukocytes (PMNL) and the exact process of the protective program employed by these cells in response to the heat shock (HS) remain ill-defined and debated. Particularly, the mechanism of phagocytic impairment induced by the HS and the molecular events associated with the delay of apoptosis used by these cells in such condition have given conflictual data. The aim of the present work is to study the consequences of the HS in different pathways involved in human PMNL apoptosis and subsequently in human PMNL phagocytic function. We demonstrated that HS (41 degrees C, 1 h) preconditioning induced inhibition of spontaneous PMNL apoptosis observed at 18 h in control cells incubated at 37 degrees C. This inhibition was characterized by absence of morphological nuclear changes, decrease of DNA fragmentation, low level of annexin V expression and decrease of caspase-3 activity. In parallel, HS increased both Hsp70 and Mcl-1 protein levels in PMNL. Phagocytosis of latex beads by PMNL was inhibited by HS (41 degrees C, 1 h) preconditioning despite an upregulation of CD11b, CD16 and CD47. Moreover, HS induced prolonged F actin depolymerization and inhibited both Rac and Cdc42 activation in PMNL. Finally, our results identify a new function of Mcl-1 in HS protection against apoptosis.
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PMID:Inhibition of apoptosis induced by heat shock preconditioning is associated with decreased phagocytosis in human polymorphonuclear leukocytes through inhibition of Rac and Cdc42. 1722 24

There are many neutrophils in the vaginal discharge from women infected with Trichomonas vaginalis. The aim of our study was to determine whether human neutrophil apoptosis may be regulated by reactive oxygen species (ROS) in response to trichomonads infection. Incubation of human neutrophils with live trichomonads caused marked receptor shedding of CD16, decrease of mitochondrial membrane potential (MMP) and caspase-3 activation in human neutrophils. These proapoptotic effects of T. vaginalis on neutrophils were inhibited by pretreatment of neutrophils with an inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI), suggesting an important role of intracellular ROS accumulation in T. vaginalis-triggered apoptosis. Indeed, large amounts of ROS levels were detected in neutrophils incubated with live trichomonads, and were also effectively inhibited by DPI. However, pan-caspase inhibitor z-VAD-fmk or caspase-3 inhibitor z-DEVD-fmk did not affect T. vaginalis-induced ROS generation in neutrophils. These results suggest that ROS-dependent caspase-3 activation plays an important role in apoptosis of human neutrophils induced by T. vaginalis.
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PMID:Trichomonas vaginalis: reactive oxygen species mediates caspase-3 dependent apoptosis of human neutrophils. 1770 5

Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56(low)CD16(+) NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL.
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PMID:Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. 1956 49

To investigate the effect of proteasomes reactivator REG gamma on cell cycle and apoptosis in vitro and in vivo. In vitro, we first constructed recombinant plasmid of PcDNA3.1-REGgamma and then transfected REGgamma into MDA-MB-231 cell line. We confirmed the transfection efficiency by Western blot. Subsequently, we observed cell growth, cycle and colony formation. Specific proliferative molecule proliferating cell nuclear antigen (PCNA) and apoptosis related signal molecule Caspase-3 was assayed by immmunohistochemistry and absorption spectrometry, respectively. In vivo, we successfully established transplantation tumor nude mice model. We determined REGgamma mRNA level in the transplantation tumor tissue. Then, FCM was used to determine cell cycle, apoptosis and CD16. Finally, we employed immunohistochemistry to determine P21 positive expression. However, the cells transfected with REGgamma grew more rapidly compared with non-transfected ones. Increased cells were observed in S+G2+M phase and S phase in the REGgamma transfected group. PCNA expression level in the transfected cells was higher than that in non-transfected ones. In vivo, we observed the similar phenomenon including more rapid tumor growth, higher REGgamma mRNA expression, decreased cells number in G0/G1 phase and G2/M phase, increased cells in S phase and decreased apoptosis in the transfected group. In the study of related molecules, we also found related molecules P21 and CD16 positive expression rate were obviously lower than non-infected ones. In present study, we found oncogenicity of MDA-MB-231 cell transfected with REGgamma was enhanced, which might be realized via REGgamma promoting cell growth, inhibiting cell apoptosis, degrading P21 and suppressing activation of NK, suggesting REGgamma promoting tumor growth is a process involving multiple factor mechanisms.
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PMID:Proteasomes reactivator REG gamma enchances oncogenicity of MDA-MB-231 cell line via promoting cell proliferation and inhibiting apoptosis. 1965 65

Neutrophils play an important role in the human immune system for protection against such microorganisms as a protozoan parasite, Trichomonas vaginalis; however, the precise role of neutrophils in the pathogenesis of trichomoniasis is still unknown. Moreover, it is thought that trichomonal lysates and excretory-secretory products (ESP), as well as live T. vaginalis, could possibly interact with neutrophils in local tissues, including areas of inflammation induced by T. vaginalis in humans. The aim of this study was to investigate the influence of T. vaginalis lysate on the fate of neutrophils. We found that T. vaginalis lysate inhibits apoptosis of human neutrophils as revealed by Giemsa stain. Less altered mitochondrial membrane potential (MMP) and surface CD16 receptor expression also supported the idea that neutrophil apoptosis is delayed after T. vaginalis lysate stimulation. In contrast, ESP stimulated-neutrophils were similar in apoptotic features of untreated neutrophils. Maintained caspase-3 and myeloid cell leukemia-1 (Mcl-1) in neutrophils co-cultured with trichomonad lysate suggest that an intrinsic mitochondrial pathway of apoptosis was involved in T. vaginalis lysate-induced delayed neutrophil apoptosis; this phenomenon may contribute to local inflammation in trichomoniasis.
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PMID:Delayed human neutrophil apoptosis by Trichomonas vaginalis lysate. 2033 79


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