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

Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Glucocorticoids (GCs) are frequently used as cotreatment because they may have potent proapoptotic properties and reduce nausea, hyperemesis, and acute toxicity on normal tissue. In contrast to the proapoptotic effect of GCs in lymphoid cells, resistance toward cancer therapy-mediated apoptosis was induced in solid tumors of human cervix and lung carcinomas. Filter hybridization, expression data, as well as functional assays identified multiple core apoptosis molecules, which are regulated by GCs in a pro- or antiapoptotic manner. Both antiapoptotic genes such as FLIP and members of the Bcl-2 and IAP family as well as proapoptotic elements of the death receptor and mitochondrial apoptosis pathways were down-regulated in carcinomas resulting in a decreased activity of caspase-8, caspase-9, and caspase-3. In contrast, death receptor and mitochondrial apoptosis signaling as well as caspase activity was enhanced by dexamethasone in lymphoid cells. To restore apoptosis sensitivity in dexamethasone-treated carcinomas, caspase-8 and caspase-9 were transfected. This resensitized tumor cells in vitro and xenografts in vivo to cisplatin induced cell death. These data therefore raise concern about the widespread combined use of GCs with antineoplastic drugs or agents in the clinical management of cancer patients.
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PMID:Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas. 1281 Jun 37

Apoptotic signaling of mammalian cells involves two pathways: the death receptor and mitochondrial pathways. In this in vivo study, we investigated apoptotic signaling of B cells in mouse germinal centers (GCs) of gut-associated lymphoid tissues (GALTs) using transmission electron microscopy (TEM), terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL), immunofluorescence of members of caspase family and cFLIP(L), and caspase activity assay. It was very difficult to ultrastructurally differentiate B cells undergoing apoptosis from B cells differentiating into memory cells or plasma cells among B cells constituting GCs. Isolated B cells in GCs showed no active form of caspase-3 or TUNEL immunoreactivity, but expressed cFLIP(L). Contrary to isolated B cells, apoptotic B cells phagocytosed by macrophages exhibited immunoreactivity of the active form of caspase-3 and TUNEL, but lacked the cFLIP(L) expression. The caspase activity assay in GALTs clearly showed intense activity of caspase-3, caspase-9, and caspace-8 that was high in order. Therefore, the death receptor pathway accompanying the increased activity of caspase-3 and caspase-8 may be blocked by the expression of cFLIP(L) in B cells of GALTs. Moreover, both the activation of caspase-3 and DNA fragmentation first occur only when B cells are phagocytosed by macrophages.
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PMID:The activation of caspase-3 and DNA fragmentation in B cells phagocytosed by macrophages. 1282 21

Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival of B and T cells. Although proper function of dendritic cells is essential to host control of invading pathogens, few studies have examined the impact of sepsis on dendritic cells. The purpose of this study was to determine the effect of sepsis on splenic interdigitating dendritic cells (IDCs) and follicular dendritic cells (FDCs) using a clinically relevant animal model. Immunohistochemical staining for FDCs showed that sepsis induced an initial marked expansion in FDCs that peaked at 36 h after onset. The FDCs expanded to fill the entire lymphoid zone otherwise occupied by B cells. Between 36 and 48 h after sepsis, there was a profound caspase 3 mediated apoptosis induced depletion of FDCs such that only a small contingent of cells remained. In contrast to the initial increase in FDCs, IDC numbers were decreased to approximately 50% of control by 12 h after onset of sepsis. IDC death occurred by caspase 3-mediated apoptosis. Such profound apoptosis induced loss of FDCs and IDCs may significantly compromise B and T cell function and impair the ability of the host to survive sepsis.
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PMID:Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. 1284 61

The pathogenesis of six Newcastle disease virus (NDV) isolates recovered from chickens (Ckn-LBM and Ckn-Australia) and wild (Anhinga) and exotic (YN parrot, pheasant, and dove) birds was examined after the isolates had been passaged four times in domestic chickens. Groups of 10 4-wk-old specific-pathogen-free white leghorn chickens were inoculated intraconjunctivally with each one of the isolates. The infected birds were observed for clinical disease and were euthanatized and sampled at selected times from 12 hr to 14 days postinoculation or at death. Tissues were examined by histopathology, by immunohistochemistry (IHC) to detect viral nucleoprotein (IHC/NP), and by in situ hybridization to detect viral mRNA and were double labeled for apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ([TUNEL] or IHC/caspase-3) and viral nucleoprorein (IHC/NP). Birds infected with the three low virulence viruses (Ckn-LBM, YN parrot, and Ckn-Australia) did not develop clinical disease. Microscopic lesions were observed only at the inoculation site and in organs of the respiratory system. The detection of viral nucleoprotein (N) was restricted to the inoculation site. The pheasant and dove isolates were highly virulent for chickens with marked tropism for lymphoid tissues, confirmed by the presence of large numbers of cells positive for viral N protein and viral mRNA. Viral N protein was detected early in the cytoplasm of cells in the center of the splenic ellipsoids. The apoptosis assays (TUNEL and IHC/caspase-3) showed increased apoptosis in the splenic ellipsoids as well. Apparently, apoptosis is an important mechanism in lymphoid depletion during NDV infection.
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PMID:Pathogenesis of chicken-passaged Newcastle disease viruses isolated from chickens and wild and exotic birds. 1288 91

Antithymocyte globulins (ATGs), the immunoglobulin G (IgG) fraction of sera from rabbits or horses immunized with human thymocytes or T-cell lines, are used in conditioning regimens for bone marrow transplantation, in the treatment of acute graft-versus-host disease, in the prevention or treatment of acute rejection in organ transplantation, and in severe bone marrow aplasia. In nonhuman primates, ATGs induce rapid, dose-dependent, T-cell depletion in peripheral lymphoid tissues, where apoptotic cells can be demonstrated in T-cell zones. We show here that increasing ATG concentrations in vitro resulted in reduced lymphocyte proliferative responses, associated with a rapid increase in the percentage of apoptotic cells. Apoptosis did not require prior exposure to interleukin-2, nor did it result in CD178/CD95 or tumor necrosis factor/tumor necrosis factor receptor (TNF/TNF-R) interactions; it was therefore clearly different from activation-induced cell death. Cytochrome c release, caspase-9, and caspase-3 activation were not implicated, excluding a direct involvement of the intrinsic mitochondrial pathway. The cysteine protease inhibitor E64d and cathepsin-B-specific inhibitors conferred significant protection, whereas apoptosis was associated with the release of active cathepsin B into the cytosol. These data demonstrate a role for cathepsin B in T-cell apoptosis induced by ATGs at concentrations achieved during clinical use.
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PMID:Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion. 1289 46

Trichothecene mycotoxins cause immunosuppression by inducing apoptosis in lymphoid tissue. Trichothecene-induced leukocyte apoptosis can be augmented by bacterial lipopolysaccharide (LPS) but the mechanisms involved in this potentiating effect are not completely understood. The objective of this study was to test the hypothesis that the trichothecene deoxynivalenol (DON, vomitoxin) can interact with LPS directly and other mediators or agonists associated with immune/inflammatory responses to induce apoptosis in primary murine leukocyte cultures. Primary leukocyte suspensions were prepared from murine thymus (TH), spleen (SP), bone marrow (BM) and Peyer's patches (PP) and then cultured with DON in the absence or presence of LPS, prostaglandin E2 (PGE2), anti-immunoglobulin (as antigen mimic), dexamethasone, Fas ligand, or TNF-alpha. Cytotoxicity and apoptosis were evaluated by MTT assay and morphologic assays, respectively. DON was found to inhibit LPS-induced proliferation and dexamethasone-induced apoptosis in SP cultures. In contrast, potentiation of DON-induced apoptosis and cytotoxicity was observed in BM cultures treated with anti-Fas and in TH cultures treated with TNF-alpha. When potentiation of DON-induced apoptosis by TNF-alpha was assessed using pharmacological inhibitors, generation of ROS, intracellular Ca2+, p38/SAPK, and caspase-3 activation were found to play roles. Taken together, these data demonstrate that LPS and its downstream mediators can interact with trichothecenes to modulate proliferative, cytotoxic and apoptotic outcomes in leukocytes in a tissue-specific manner.
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PMID:Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. 1459 25

Chlamydiae are obligate intracellular bacteria that infect human epithelial and myeloid cells. Previous work has established that chlamydiae are able to protect a cell against apoptosis induced by certain experimentally applied stimuli. Here we provide an analysis of this protective activity against the signal transduction during CD95-induced apoptosis. In HeLa cells overexpressing CD95, infection with Chlamydia trachomatis inhibited the appearance of apoptotic morphology, effector caspase activity, the activation of caspase-9 and -3, and the release of cytochrome c from mitochondria. However, caspase-8-processing and activity (measured as cleavage of Bid) were unaffected by the chlamydial infection. Similarly, infection with the species C. pneumoniae did not prevent the activation of caspase-8 but inhibited the appearance of effector caspase activity upon signaling through CD95. Furthermore, infection with C. trachomatis was able to inhibit CD95-induced apoptosis in Jurkat lymphoid cells, where a mitochondrial contribution is required, but not in SKW6.4 lymphoid cells, where caspase-8 directly activates caspase-3. Taken together, these data show that chlamydial infection can protect cells against CD95-induced apoptosis but only where a mitochondrial signaling step is necessary for apoptotic signal transduction.
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PMID:Protection against CD95-induced apoptosis by chlamydial infection at a mitochondrial step. 1474 58

In the present study, we have focused on the specific question of whether ultrasound application (ULS) delivered with optimized parameters for cavitation generation can stimulate apoptosis in lymphoid cell lines. Suspended T and B lymphoid cell lines (Jurkat and Raji, respectively) were exposed to low frequency ULS (750 KHz) at an intensity level of 54.6 W/cm(2) spatial peak temporal average (SPTA) at focal area, which was found to be the optimal physical parameter to induce apoptosis in these malignant cell lines. Unsonicated cells and cells exposed to gamma-radiation (20 Gy) using (137)Cs source were used as control. Apoptosis was evaluated by cell morphology changes, cell-cycle analysis, and phosphatidylserine exposure. Fraction of cells with low mitochondria membrane potential was observed 1 h after sonication, accompanied by cytochrome c release from mitochondria to the cytosol and caspase-3 activation. Here we present evidence that ULS exposure with cavitation formation on malignant lymphoid cell lines differs from gamma-radiation and is associated with time-dependent apoptosis, which is mitochondria-caspase dependent.
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PMID:Induction of apoptosis by ultrasound application in human malignant lymphoid cells: role of mitochondria-caspase pathway activation. 1503 13

Ochratoxin A (OTA) is a widespread mycotoxin contaminating feed and food. Besides its potent nephrotoxicity, OTA also affects the immune system. We demonstrate here a role for Bcl-x(L) in OTA-induced apoptosis in human lymphocytes. In particular, human peripheral blood lymphocytes and the human lymphoid T cell line, Kit 225 cells, underwent apoptosis in a time- and dose-dependent manner. This apoptosis was inhibited by z-VAD.fmk, suggesting that caspases were responsible for the induction of apoptosis. Moreover, OTA triggered mitochondrial transmembrane potential (Deltachim) loss and caspase-9 and caspase-3 activation. Interestingly, Bcl-x(L) protein expression was decreased by OTA treatment, whereas Bcl-2 protein level was not affected. Down-regulation of bcl-x(L) mRNA was not observed in cells treated with OTA. Overexpression of Bcl-x(L) in Kit 225 cells protected them against mitochondrial perturbation and retarded the appearance of apoptotic cells. Taken together, our data indicate that mitochondria are a central component in OTA-induced apoptosis and that the loss of Bcl-x(L) may participate in OTA-induced cell death.
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PMID:Ochratoxin A induces apoptosis in human lymphocytes through down regulation of Bcl-xL. 1505 5

The frequency and the distribution of apoptotic cells were investigated in formalin-fixed paraffin-embedded lymphoid tissues from healthy conventional pigs at four different ages (6 days, 2 months, 3.5 months and 5 months). Samples of tonsil, mesenteric lymph node, spleen, thymus and Peyer's patches were histologically processed and apoptosis evaluated with the TUNEL reaction and cleaved caspase-3 immunohistochemistry. In each technique, quantification of positive labelling was done for each particular lymphoid tissue area. The labelling pattern and distribution were similar for TUNEL and cleaved caspase-3. TUNEL stained mainly apoptotic bodies inside macrophages, but signal was also seen in free apoptotic bodies and in the nuclei of lymphocyte-like cells. The anti-cleaved caspase-3 antibody labelled mainly nuclei of lymphocyte-like cells. All tissues presented a similar distribution pattern of apoptosis, except for the 6-day-old group. In this group, a scattered distribution of positive cells was detected in tonsil, lymph node and spleen. In the tonsil and mesenteric lymph nodes from the older pigs, follicular areas presented higher amounts of positive cells than interfollicular areas. Moreover, the splenic white pulp showed more positive reaction than the red pulp, especially when they included germinal centres. In all groups, the follicular areas of ileal Peyer's patches presented more labelled cells than the dome and the lamina propria. In the thymus, the higher apoptotic rates were found in the cortex. In general, TUNEL yielded higher rates of positive cells than cleaved caspase-3 immunolabelling. A good correlation between the two techniques was found for thymus, tonsil and mesenteric lymph node, but not for Peyer's patches and spleen. This study describes a detailed histochemical characterization of apoptosis in pig lymphoid tissues using TUNEL and a cleaved caspase-3 immunolabelling at different ages. Moreover, our results indicate that TUNEL and cleaved caspase-3 techniques can be equivalent only when tissues have a high or low levels of apoptosis, since a considerable discrepancy was found in intermediate situations. Data from this study should be useful for future comparative studies under disease conditions.
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PMID:Apoptosis in normal lymphoid organs from healthy normal, conventional pigs at different ages detected by TUNEL and cleaved caspase-3 immunohistochemistry in paraffin-embedded tissues. 1513 86


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