Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human gastric carcinoma cell line HSC-39 has been shown to undergo apoptotic cell death in response to treatment with transforming growth factor beta1 (TGF-beta1). To understand better the cell death mechanism in this TGF-beta1-mediated apoptosis, we investigated the effect of the expression of TGF-beta-stimulated clone 22 (TSC-22) on cell death events. TGF-beta1 induced TSC-22 gene expression in HSC-39 cells only when the cells had previously been adapted to the serum-free culture conditions required to undergo TGF-beta1-mediated apoptosis. HSC-39 cells transfected with a TSC-22 expression vector showed a significant decrease in cell viability compared with those transfected with a control vector. The cellular events characteristic of apoptosis, chromatin condensation and DNA fragmentation were observed only in cells transfected with a TSC-22 expression vector. On immunostaining of the transfected cells, almost every cell that expressed TSC-22 tagged with influenza virus haemagglutinin exhibited the morphology of an apoptotic cell. Partial protection from the cell death effect of TGF-beta1 on HSC-39 cells was observed when cells were treated with acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspart-1-al (Ac-DEVD-CHO, an inhibitor specific for CPP32-type protease). Protection against cell death by the transfection of a TSC-22 expression vector was also offered by Ac-DEVD-CHO addition. These results suggest that TSC-22 elicits the apoptotic cell death of human gastric carcinoma cells through the activation of CPP32-like protease and mediates the TGF-beta1 signalling pathway to apoptosis.
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PMID:Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor beta. 921 Apr

Influenza virus infection induces apoptosis in cultured cells with an augmented expression of Fas (APO-1/CD95). Caspases, a family of cysteine proteases structurally related to interleukin-1-beta-converting enzyme (ICE), play crucial roles in apoptosis induced by various stimuli, including Fas. However, activation of the caspase-cascade seems to be different in various pathways of apoptotic stimuli. We therefore examined the involvement of caspases in influenza virus-induced apoptosis using caspase inhibitors. We found that z-VAD-fmk and z-IETD-fmk effectively inhibited virus-induced apoptosis, whereas Ac-DEVD-CHO and Ac-YVAD-CHO showed partial and little effect on virus-induced cell death, respectively. Consistently, caspase-3-like activity, but not caspase-1-like activity, was increased in the virus-infected cells. The transfection of plasmids encoding viral inhibitors of caspase (v-FLIP or crmA) into HeLa cells inhibited apoptosis by virus infection. The peptide inhibitors of caspases used in this study did not inhibit viral replication. We conclude that influenza virus infection activates some caspases, and that this activation may be downstream of viral replication.
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PMID:Recruitment of apoptotic cysteine proteases (caspases) in influenza virus-induced cell death. 1033 94

Bacterial superinfections are an important cause of morbidity and mortality during influenza A virus (IAV) epidemics. We demonstrate that incubation with the combination of IAV and Streptococcus pneumoniae caused marked reductions in survival of neutrophils in vitro compared with treatment with control buffer or IAV or S. pneumoniae alone. This cooperative effect was in part mediated by acceleration of neutrophil apoptosis as evidenced by increases in annexin-V binding and caspase-3 activation. However, GM-CSF did not increase survival of neutrophils exposed to IAV and S. pneumoniae. IAV enhanced neutrophil uptake of S. pneumoniae significantly. Furthermore, the combination of IAV and S. pneumoniae caused significantly more hydrogen peroxide production than IAV or S. pneumoniae alone. This increased respiratory burst activity contributed to the diminished neutrophil survival caused by IAV and S. pneumoniae. The NADPH oxidase inhibitor, diphenyleneiodonium, significantly improved survival of neutrophils treated with IAV and S. pneumoniae. These findings may help to explain the increased susceptibility of IAV-infected patients to infections with S. pneumoniae.
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PMID:Neutrophil survival is markedly reduced by incubation with influenza virus and Streptococcus pneumoniae: role of respiratory burst. 1120 67

There is increasing evidence that IL-18 is a key pro-inflammatory cytokine and an important mediator of Th1 immune response. The main source of IL-18 is macrophage-like cells. In the present study we have investigated IL-18 protein expression in primary human macrophages in response to influenza A and Sendai virus infections. Macrophages constitutively expressed proIL-18 but produced biologically active IL-18 only after virus infection. The IL-18 release was due to virus infection-induced proteolytic processing of 24-kDa proIL-18 into its mature 18-kDa form. ProIL-18 processing required active caspase-1 enzyme and the release of mature IL-18 was blocked with a caspase-1-specific inhibitor. Caspase-3 inhibitor also reduced IL-18 production in response to virus infection. Inactive proforms of caspase-1 and caspase-3 were basally expressed in macrophages, and virus infection induced the cleavage of procaspases into their mature forms. Besides increasing the expression of caspase proteins, virus infection enhanced caspase mRNA expression in macrophages. The enhancement of caspase gene expression was abrogated by anti-IFN-alpha antibody. Furthermore, IFN-alpha and IFN-gamma could induce caspase gene expression. These results imply that interferons are involved in virus-induced caspase activation that leads to proIL-18 processing and subsequent release of mature IL-18.
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PMID:Virus infection induces proteolytic processing of IL-18 in human macrophages via caspase-1 and caspase-3 activation. 1124 Dec 76

Infection of humans with influenza A virus (IAV) results in a severe transient leukopenia. The goal of these studies was to analyze possible mechanisms behind this IAV-induced leukopenia with emphasis on the potential induction of apoptosis of lymphocytes by the virus. Analysis of lymphocyte subpopulations after exposure to IAV showed that a portion of CD3(+), CD4(+), CD8(+), and CD19(+) lymphocytes became apoptotic (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling positive). The percentage of cells that are infected was shown to be less than the percentage of apoptotic cells, suggesting that direct effects of cell infection by the virus cannot account fully for the high level of cell death. Removal of monocytes-macrophages after IAV exposure reduced the percent of lymphocytes that were apoptotic. Treatment of virus-exposed cultures with anti-tumor necrosis factor alpha did not reduce the percentage of lymphocytes that were apoptotic. In virus-exposed cultures treated with anti-FasL antibody, recombinant soluble human Fas, Ac-DEVD-CHO (caspase-3 inhibitor), or Z-VAD-FMK (general caspase inhibitor), apoptosis and production of the active form of caspase-3 was reduced. The apoptotic cells were Fas-high-density cells while the nonapoptotic cells expressed a low density of Fas. The present studies showed that Fas-FasL signaling plays a major role in the induction of apoptosis in lymphocytes after exposure to IAV. Since the host response to influenza virus commonly results in recovery from the infection, with residual disease uncommon, lymphocyte apoptosis likely represents a part of an overall beneficial immune response but could be a possible mechanism of disease pathogenesis.
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PMID:Human lymphocyte apoptosis after exposure to influenza A virus. 1139 May 93

Equine influenza virus (EIV) is the leading cause of acute respiratory infection in horses worldwide. In recent years, the precise mechanism by which influenza infection kills host cells is being re-evaluated. In this report, we examined whether caspases, a group of intracellular proteases, are activated following EIV infection and contribute to EIV-mediated cell death. Western blotting analysis indicated that a nuclear target of caspase-3, poly(ADP-ribose) polymerase (PARP) was proteolytically cleaved in EIV-infected MDCK cells, but not in mock-infected cells. In comparison with caspase-3 specific inhibitor Ac-DEVD-CHO, a general caspase inhibitor Boc-D-FMK provided much stronger inhibition of EIV-induced cytopathic effect and apoptosis. Our results suggest that EIV may activate more than one caspase. Caspase activation and cleavage of its cellular targets may play a critical role in EIV-mediated cytotoxicity.
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PMID:Caspase activation in equine influenza virus induced apoptotic cell death. 1175 Jan 43

Influenza A virus (IAV)-induced impairment of neutrophil function or survival may be a cause of bacterial superinfection of IAV-infected subjects. This study was performed to determine the mechanism through which the combination of IAV and Escherichia coli co-operatively reduces neutrophil survival. Neutrophil binding of annexin-V and caspase-3 activation was significantly increased by either IAV or E. coli, supporting the concept that the micro-organisms accelerate neutrophil apoptosis. The anti-apoptotic agent granulocyte-macrophage colony stimulating factor (GM-CSF) did not improve, but further reduced, survival of neutrophils treated with IAV and E. coli. As addition of E. coli resulted in greater neutrophil uptake of IAV and greater neutrophil respiratory burst responses to IAV, this study tested whether respiratory burst activation by IAV and E. coli contributes to reducing neutrophil survival. The cell-permeant NADPH oxidase inhibitor, diphenylene iodonium, significantly increased survival of neutrophils treated with either E. coli alone or the combination of IAV and E. coli. In contrast, catalase, which is not cell permeant, did not alter survival of E. coli- and IAV-treated neutrophils. Azide enhanced neutrophil hydrogen peroxide responses to IAV and E. coli, and reduced survival of these cells. These results indicate that co-operative induction of intracellular respiratory burst responses by IAV and E.coli mediates the reduced neutrophil survival caused by these pathogens in vitro.
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PMID:Role of the respiratory burst in co-operative reduction in neutrophil survival by influenza A virus and Escherichia coli. 1201 55

Olfactory receptor neurons (ORNs) were infected upon intranasal inoculation with the R404BP strain of neurovirulent influenza A virus. Virus-infected neurons and a small fraction of neighbouring uninfected neurons displayed apoptotic neurodegeneration substantiated by the immunohistochemistry for activated caspase-3 molecules and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling method. However, virus infection was restricted within the peripheral neuroepithelium and all mice survived the infection. Virus-infected ORNs revealed upregulated expression of the Fas ligand molecules, activating the c-Jun N-terminal kinase signal transduction pathway. In addition, Iba1-expressing activated microglia/macrophages appeared to partake in phagocytic activities, eventually clearing apoptotic bodies. These results raise the possibility that induction of apoptosis in olfactory receptor neurons at an early stage of infection may provide protective effects against invasion of the neurovirulent virus from the peripheral to the CNS.
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PMID:Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis. 1218 63

Apoptosis occurs in influenza virus (IV)-infected cells. There are a number of mechanisms for the regulation of apoptosis. However, the molecular mechanism of IV infection-induced apoptosis is still controversial. Apoptosis signal-regulating kinase1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the SEK1-c-Jun N-terminal kinase (JNK) and MKK3/MKK6-p38 MAPK signaling cascades. ASK1 has been implicated in cytokine- and stress-induced apoptosis. Here, we show the following: (1) IV infection activated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells; (2) the activation of JNK and p38 MAPK but not extracellular-regulated kinase (ERK) in embryonic fibroblasts (MEFs) derived from ASK1 knockout mice (ASK1(-/-) MEFs) was depressed compared to MEFs derived from wild type mice (ASK1(+/+) MEFs); and (3) ASK1(-/-) MEFs were defective in IV infection-induced caspase-3 activation and cell death. These results indicate that apoptosis in IV-infected BEC is mediated through ASK1-dependent cascades.
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PMID:ASK1 regulates influenza virus infection-induced apoptotic cell death. 1287 92

The temporal and spatial distribution of active c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in the brain was investigated in an experimental virus-mouse system in which neurovirulent influenza A virus caused lethal acute encephalitis. Following stereotaxic microinjection into the olfactory bulb, virus-infected neurons appeared in several midbrain structures, including the ventral tegmental area, amygdala and the pyramidal layer of the hippocampus. Infected neurons exhibited apoptosis on day 5, as demonstrated by in situ detection of DNA fragmentation and active caspase-3. The stress-responsive JNK signal transduction pathway was activated in virus-infected neurons. Activation of p38 MAPK was widespread and occurred in astrocytes on day 7 after infection. Active p38 MAPK in astrocytes showed no association with apoptosis but appeared to be involved in regulation of TNF-alpha production. These results indicate that these two stress-activated protein kinases may play distinct roles during the course of lethal acute influenza virus encephalitis.
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PMID:Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus. 1291 61


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