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)

Cytokeratin 18 (CK18) protein was identified as an airway epithelial cell autoantigen associated with nonallergic asthma. Cleavage of CK18 protein by caspase-3 is a marker of early apoptosis in epithelial cells. It has been shown that the expression of active caspase-3 was increased in bronchial epithelial cells of asthmatic patients, when compared with healthy controls. To investigate the antigen-binding characteristics of IgG autoantibodies to CK18 protein in nonallergic asthma, the bindings of IgG autoantibodies to the fragments of CK18 protein cleaved by caspase-3 were analyzed by Western blot using serum samples from three patients with nonallergic asthma. Recombinant human CK18 protein was treated by caspase-3 and cleaved into N-terminal fragment (1-397 amino acids) and C-terminal fragment (398-430 amino acids). The binding capacity of IgG autoantibodies to N-terminal fragment of CK18 was maintained in one patient and reduced in other two patients. IgG autoantibodies from all three patients did not bind to C-terminal fragment of CK 18. In conclusion, IgG autoantibodies to CK18 protein from patients with nonallergic asthma seems to preferentially bind to the whole molecule of CK18 protein and their antigen-binding characteristics were heterogeneous among the patients with nonallergic asthma.
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PMID:Antigen-binding characteristics of circulating IgG autoantibodies to cytokeratin 18 protein in patients with nonallergic asthma. 1689 8

Reactive nitrogen species (RNS) are implicated in the pathophysiology of inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease. The molecular mechanisms and signaling events involved in lung cell injury by RNS are still poorly understood. In the current study, we observe a novel anti-apoptotic response to nitric oxide (NO) exposure (via the NO donors 3-morpholine-syndnonimine (SIN1) or papa-NONOate) of human airway epithelial (HAE) cells. NO exposure via the NO donors increased cellular ceramide levels via ceramide synthase but did not trigger an apoptotic response. Rather, exposure to the NO donors promoted an increase in the protein-protein interaction between acidic sphingomyelinase (aSMase) and caspase-3, with aSMase sequestering caspase-3 and preventing its cleavage. In contrast, when aSMase was silenced in HAE cells or was knocked out in mice, an increase in cleaved caspase-3 was observed. This elevated caspase-3 cleavage was further augmented upon NO exposure (via SIN1 or papa-NONOate) of HAE cells and could be prevented by an inhibitor to ceramide synthase. These results demonstrate a novel mechanism of NO modulation of apoptosis, in which HAE cells exposed to NO via an NO donor induces ceramide generation via ceramide synthase. However, this ceramide induction does not lead to apoptosis unless aSMase is knocked down, allowing the release of caspase-3, its activation and execution of apoptosis.
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PMID:Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: a novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis. 1723 51

The high-affinity IgE receptor (FcepsilonRI) has recently been reported to be expressed by neutrophils in atopic asthmatic individuals, leading to speculations that IgE could influence biological functions of these cells. In this study, we demonstrate that monomeric human IgE delayed spontaneous apoptosis of primary human neutrophils from atopic asthmatics in vitro. This effect was not dependent on FcepsilonRI cross-linking or autocrine release of soluble mediators; however, it was associated with increased expression of the antiapoptotic myeloid cell leukemia-1 protein, retention of the proapoptotic molecule Bax in the cytoplasm, decreased release of Smac from mitochondria, and reduced caspase-3 activity. Taken together, our results indicate that in vitro IgE can delay programmed cell death of neutrophils from allergic asthmatics and this may possibly contribute to neutrophilic inflammation in atopic asthma.
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PMID:IgE modulates neutrophil survival in asthma: role of mitochondrial pathway. 1727 62

The cellular effects of biodiesel emissions particulate matter (BDEP) and petroleum diesel emissions particulate matter (PDEP) were compared using a human airway cell line, A549. At concentrations of 25 microg/ml, diesel particulate matter induced the formation of multinucleate cells. In cells treated with a mixture of 80% PDEP:20% BDEP, 52% of cells were multinucleate cells compared with only 16% of cells treated with 20% PDEP:80% BDEP with a background multinucleate rate of 7%. These results demonstrate a causal relation between the formation of multinucleate cells and exposure to exhaust particulate matter, in particular diesel exhaust. Exposure of A549 cells to PDEP induced apoptosis, seen by active caspase-3 expression and the presence of cleaved pancytokeratin. PDEP exhaust was a much stronger inducer of cellular death through apoptosis than BDEP. There was an eightfold increase in the expression of SLC30A3 (zinc transporter-3 or ZnT3) in cells exposed to 80% PDEP:20% BDEP compared to untreated cells. The increase in ZnT3 expression seen in apoptotic cells following PDEP suggests a role for this zinc transporter in the apoptotic pathway, possibly through controlling zinc fluxes. As exposure to diesel exhaust particles is associated with asthma and apoptosis in airway cells, diesel exhaust particles may directly contribute to asthma by inducing epithelial cell death through apoptotic pathway.
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PMID:Diesel exhaust particulate matter induces multinucleate cells and zinc transporter-dependent apoptosis in human airway cells. 1768 10

Previously, we have identified the sequential activation of reactive oxygen species (ROS), mitochondria, and caspase-3, -8, and -9, in Siglec-8-mediated eosinophil apoptosis. Cytokine priming, which normally prolongs eosinophil survival, paradoxically potentiated this proapoptotic effect. The mechanisms of Siglec-8-mediated apoptosis after priming were therefore explored. Using IL-5 as the priming stimulus, the rate of Siglec-8-induced eosinophil apoptosis was found to be enhanced compared with unprimed cells, and mechanisms differed after IL-5 priming in that neither a pan-caspase inhibitor, nor a specific caspase-3 inhibitor, could override apoptosis. IL-5 priming also accelerated Siglec-8-mediated dissipation of mitochondrial membrane potential. Finally, both the mitochondrial electron transport inhibitor rotenone, and the ROS inhibitors diphenyleneiodonium and antimycin, completely inhibited Siglec-8-mediated apoptosis, even after IL-5 priming. These data demonstrate that IL-5 priming enhances Siglec-8-mediated mitochondrial and ROS-dependent eosinophil apoptosis and eliminates caspase dependence. The potential clinical implication of these findings is that cytokine priming, as often occurs in vivo in asthma and other hypereosinophilic disorders, may render eosinophils from such patients especially susceptible to the proapoptotic effects of a Siglec-8-engaging therapeutic agent.
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PMID:Interleukin-5 priming of human eosinophils alters siglec-8 mediated apoptosis pathways. 1769 Mar 26

IL-33 is a chromatin-associated cytokine of the IL-1 family that has recently been linked to many diseases, including asthma, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. IL-33 signals through the IL-1 receptor-related protein ST2 and drives production of pro-inflammatory and T helper type 2-associated cytokines in mast cells, T helper type 2 lymphocytes, basophils, eosinophils, invariant natural killer T cells, and natural killer cells. It is currently believed that IL-33, like IL-1beta and IL-18, requires processing by caspase-1 to a mature form (IL-33(112-270)) for biological activity. Contrary to the current belief, we report here that full-length IL-33(1-270) is active and that processing by caspase-1 results in IL-33 inactivation, rather than activation. We show that full-length IL-33(1-270) binds and activates ST2, similarly to IL-33(112-270), and that cleavage by caspase-1 does not occur at the site initially proposed (Ser(111)), but rather after residue Asp(178) between the fourth and fifth predicted beta-strands of the IL-1-like domain. Surprisingly, the caspase-1 cleavage site (DGVD(178)G) is similar to the consensus site of cleavage by caspase-3, and IL-33 is also a substrate for this apoptotic caspase. Interestingly, we found that full-length IL-33, which is constitutively expressed to high levels by endothelial cells in most normal human tissues, can be released in the extracellular space after endothelial cell damage or mechanical injury. We speculate that IL-33 may function, similarly to the prototypical alarmins HMGB1 and IL-1alpha, as an endogenous danger signal to alert cells of the innate immune system of tissue damage during trauma or infection.
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PMID:The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. 1943 63

Wood dusts are associated with several respiratory symptoms, e.g. impaired lung function and asthma, in exposed workers. However, despite the evidence from epidemiological studies, the underlying mechanisms are not well understood. In the present study, we investigated different wood dusts for their capacity to induce cytotoxicity and production of radical oxygen species (ROS) as well as activation of the apoptotic caspase-3 enzyme in human bronchial epithelial cells (BEAS-2B). Dusts from three different tree species widely used in wood industry were studied; birch and oak represented hardwood species, and pine a common softwood species. All the experiments were carried out in three different concentrations (10, 50, and 500 microg/ml) and the analysis was performed after 0.5, 2, 6, and 24h exposure. All wood dusts studied were cytotoxic to human bronchial epithelial cells in a dose-dependent manner after 2 and 6h treatment. Exposure to pine, birch, or oak dust had a significant stimulating effect on the production of ROS. Also an induction in caspase-3 protease activity, one of the central components of the apoptotic cascade, was seen in BEAS-2B cells after 2 and 6h exposure to each of the wood dusts studied. In summary, we demonstrate that dusts from pine, birch and oak are cytotoxic, able to increase the production of ROS and the apoptotic response in human broncho-epithelial cells in vitro. Thus, our current data suggest oxidative stress by ROS as an important mechanism likely to function in wood dust related pulmonary toxicity although details of the cellular targets and cell-particle interactions remain to be solved. It is though tempting to speculate that redox-regulated transcription factors such as NFkappaB or AP-1 may play a role in this wood dust-evoked process leading to apparently induced apoptosis of target cells.
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PMID:Wood dusts induce the production of reactive oxygen species and caspase-3 activity in human bronchial epithelial cells. 1957 73

Eosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide staining, morphological analysis by light microscopy, transmission electron microscopy and Western immunoblotting for caspase-3 cleavage. We further dissect these observations by demonstrating that eosinophils treated with R-roscovitine lose mitochondrial membrane potential and the key survival protein Mcl-1 is down-regulated. This novel finding of efficacious induction of eosinophil apoptosis by CDKi drugs has potential as a strategy for driving resolution of eosinophilic inflammation.
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PMID:The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1. 1961 48

Rhinoviruses are prevalent human pathogens that are associated with life-threatening acute asthma exacerbations. The innate immune response to rhinovirus infection, which may play an important role in virus-induced asthma induction, has not been comprehensively investigated. We examined the innate immune response in cells infected with human rhinovirus 1a (HRV1a). Beta interferon (IFN-beta) mRNA was induced in HRV1a-infected cells at levels significantly lower than in cells infected with Sendai virus. To understand the basis for this observation, we determined whether components of the pathway leading to IFN-beta induction were altered during infection. Dimerization of the transcription factor IRF-3, which is required for synthesis of IFN-beta mRNA, is not observed in cells infected with HRV1a. Beginning at 7 h postinfection, IPS-1, a protein that is essential for cytosolic sensing of viral RNA, is degraded in HRV1a-infected cells. Induction of apoptosis by puromycin led to the cleavage of IPS-1, but treatment of HRV1a-infected cells with the pan-caspase inhibitor, zVAD, did not block cleavage of IPS-1. IPS-1 is cleaved in vitro by caspase-3 and by the picornaviral proteinases 2A(pro) and 3C(pro). Expression of HRV1a and polioviral 2A(pro) and 3C(pro) led to degradation of IPS-1 in cells. These results suggest that IPS-1 is cleaved during HRV1a infection by three different proteases. Cleavage of IPS-1 may be a mechanism for evasion of the type I IFN response, leading to a more robust infection.
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PMID:Cleavage of IPS-1 in cells infected with human rhinovirus. 1974 Sep 98

Interleukin-16 (IL-16) is a pro-inflammatory cytokine released by many types of cells found in the lungs, including normal airway and alveolar epithelial cells. Though a chemotactin for CD4(+) cells and eosinophils, IL-16 also modulates their production of factors that influence inflammatory lung diseases, e.g., asthma and allergic rhinitis. To date, little is known about any potential autocrine-like regulatory effects of IL-16. Using a model human alveolar basal epithelial A549 cell line, the present study sought to assess lung epithelial cell responses to IL-16. Potential induced effects on cell growth/function were assessed using MTT reduction, lactate dehydrogenase release, and 5-bromo-2-deoxyuridine incorporation assays. As IL-16 (at locally high levels) can induce CD4(+) cell death via apoptosis, this potential outcome among the A549 cells was also evaluated using TUNEL and changes in expression of caspase-3 and the pro-apoptotic and anti-apoptotic proteins of Bcl-2 family. The data here indicated that IL-16 inhibited A549 cell growth/function and this was associated with a marked increase in apoptosis characterized by DNA fragmentation, activation of caspase-3, and altered pro-apoptotic protein expression. Since lung epithelial cells lack the CD4 that may bind IL-16, it has been suggested that CD9 may act as an alternate receptor for this cytokine (i.e., an IL-16R). Thus, these studies also sought to determine the extent of CD9 expression on A549 cells and if any/all observed IL-16-induced changes were mediated by CD9. Flow cytometric analyses revealed the cells to be CD9(+)CD4(-). However, neutralization of the purported IL-16R with anti-CD9 antibody could not block the cytotoxic/growth inhibiting effects of IL-16. The only exception appeared to be a mitigation of a chemotactic effect of IL-16; however, studies with an equal amount of non-specific antibody (of same isotype as the anti-CD9) revealed this effect to be artefactual. The neutralization study results thus suggest to us that as-yet undefined pathway(s) exist through which IL-16 may act to exert growth inhibiting/apoptosis-inducing effects on A549 cells, a cell line routinely used as a model for lung epithelial cells.
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PMID:IL-16 effects on A549 lung epithelial cells: dependence on CD9 as an IL-16 receptor? 2030 49


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