Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is currently unclear whether Shigella kills its phagocytic host cells by apoptosis or necrosis. This study shows that rapid necrosis ensues in macrophage-like cell lines (U937 cells differentiated by all-trans-retinoic acid and J774 cells) infected with the Shigella flexneri strain YSH6000. The infected cells rapidly lose membrane integrity, a typical feature of necrosis, as indicated by the release of the cytoplasmic lactate dehydrogenase and the exposure of phosphatidylserine (PS) associated with the rapid uptake of propidium iodide (PI). The infected cells exhibit DNA fragmentation without nuclear condensation, and substantial involvement of either caspase-3/-7 or caspase-1 was not detected, which is also contrary to what is normally observed in apoptosis. Cytochalasin D potently inhibited Shigella-induced cell death, indicating that only internalized Shigella can cause necrosis. Osmoprotectants such as polyethylene glycols could suppress cell death, suggesting that insertion of a pore by Shigella into the host cell membrane induces the necrosis. The pore was estimated to be 2.87+/-0.4 nm in diameter. Shigella was also found to be able to induce apoptosis but only in one of the lines tested and under specific conditions, namely U937 cells differentiated with interferon-gamma (U937IFN). Caspase-3/-7 but not caspase-1 activation was observed in these infected cells and the exposure of PS occurred without the uptake of PI. An avirulent Shigella strain, wild-type Shigella killed with gentamicin, and even Escherichia coli strain JM109, could also induce apoptosis in U937IFN cells, and cytochalasin D could not prevent apoptosis. It appears therefore that Shigella-induced apoptosis of U937IFN cells is unrelated to Shigella pathogenicity and does not require bacterial internalization. Thus, Shigella can induce rapid necrosis of macrophage-like cells in a virulence-related manner by forming pores in the host cell membrane while some cells can be killed through apoptosis in a virulence-independent fashion.
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PMID:Shigella-induced necrosis and apoptosis of U937 cells and J774 macrophages. 1294 76

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly inhibits lung metastatic colony formation, and that this inhibition was possibly due to the activation of T and NK cells. Furthermore, we found that interleukin-18 (IL-18) is induced in epithelial cells of the small intestine by bLF. The present study was undertaken to confirm cytokine production in response to bLF and to assess the underlying mechanisms. Markedly elevated IL-18 levels were found in the small intestine 1-3 h after a single administration of bLF, its pepsin hydrolysate (bLFH), or bTF. Importantly, while IL-18 was significantly increased after a regimen of seven daily administrations of bLF or bLFH, administration of bTF over the course of seven days had little or no effect. In addition to IL-18, a significant increase in caspase-1 activity and interferon-gamma (IFN-gamma) was found in the small intestine after administration of bLF. Similarly, in peritoneal macrophages, bLF markedly enhanced caspase-1 activity and IL-18 levels. Finally, a caspase-1 inhibitor significantly decreased bLF mediated induction of IL-18 in vitro. (bTF had no effect on either caspase-1 or IFN-gamma or on IL-18 in vitro.) These results demonstrate the possibility that elevation of caspase-1 activity by bLF and its hydrolysate may be important for production of mature IL-18 in vivo, and thus in potentiating the killing activity of T and NK cells against tumor cells.
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PMID:Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis. 1468 84

Cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), can initiate dual effects resulting in either cell growth or cell death. In this study, the human oligodendroglial cell lines HOG and MO3.13 were used as a model to study the molecular mechanisms of cytokine-induced cell death in human oligodendrocytes. We have previously shown that TNF-alpha and IFN-gamma induce apoptosis in both oligodendroglial cell lines within 72 hr. In the present study, the cell death pathways operating within these cells were further investigated at the gene expression level. Both cell lines express a broad repertoire of caspases and apoptosis-related genes. Some of these genes are specifically up-regulated by cytokine treatment; e.g., caspase-1 is up-regulated by IFN-gamma. In addition to direct cytotoxic effects, IFN-gamma and TNF-alpha also enhance the expression of Fas, TNFR1, and MHC class I molecules in both cell lines. This suggests that cytokines can make oligodendrocytes more vulnerable to different cell death pathways in an inflammatory environment. cDNA microarray analysis of the HOG cell line revealed that TNF-alpha induces genes that regulate apoptosis, survival, inflammation, cell metabolism, and cell signaling. The data suggest that oligodendroglial cells activate both death and survival pathways upon cytokine challenges. However, the survival pathways seem to be unable to compete with the death signal after more than 24 hr of cytokine treatment. These results may contribute to the development of therapeutic strategies aimed at interfering with cytokine-induced cell death of oligodendrocytes in patients with multiple sclerosis.
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PMID:Cytokine-induced cell death in human oligodendroglial cell lines. II: Alterations in gene expression induced by interferon-gamma and tumor necrosis factor-alpha. 1516 Mar 96

Interleukin-18 (IL-18) is a single-chain cytokine that is produced by various cells. With interleukin-12 (IL-12), it synergistically stimulates activated T cells and natural killer (NK) cells to produce interferon-gamma (IFN-gamma). Nasopharyngeal carcinoma (NPC) is the most common form of nasal and nasopharyngeal malignancy, and in NPC tumor tissues there is an intense leukocyte infiltration comprising predominantly T cells and macrophages. We previously showed an increased expression of IFN-gamma in the infiltrating T cells. To identify the cells that provide IL-12 and IL-18 for stimulating the expression of IFN-gamma in activated T cells, NPC cell lines CNE-2 and HK-1, as well as biopsies obtained from NPC and control individuals, were examined. CNE-2 and HK-1 cells were found to express messenger RNA encoding IL-18, but not IL-12. Secreted IL-18 was detected in the culture supernatant. Addition of a caspase-1 inhibitor decreased the secretion level, indicating that this IL-18 secretion was caspase-1 dependent. Moreover, the in vitro IL-18 production in NPC cell lines correlated with the NPC tumor cells in situ. NPC tumor cells in the biopsies produced IL-18, as detected by immunohistochemistry and immunofluorescent double staining. In contrast, IL-18 expression was not observed in the control biopsies. We suggest that IL-18 secreted by NPC tumor cells plays a role in initiating the leukocyte infiltration process. IL-18 stimulates T cells and NK cells to produce IFN-gamma, which consequently activates macrophages and other immune cells to secrete chemokines to start a leukocyte recruitment cascade.
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PMID:Expression of interleukin-18 by nasopharyngeal carcinoma cells: a factor that possibly initiates the massive leukocyte infiltration. 1518 38

Mutations in the gene coding for the ubiquitous, anti-oxidant enzyme Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), a fatal disease characterized by selective loss of motor neurons. Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or astrocytes is insufficient to generate a pathological phenotype in mouse models, suggesting that a deleterious interplay between different cell types is necessary for the pathogenesis of the disease. In this study, we demonstrate the actual role of a functional cross-talk between glial and neuronal cells expressing fALS mutant G93A-SOD1, where an increase in the production of reactive oxygen species occurs. We show that human glioblastoma cells expressing G93A-SOD1 induce activation of caspase-1, release of cytokines, and activation of apoptotic pathways in cocultured human neuroblastoma cells also expressing G93A-SOD1. Activation of caspase-1 and caspase-3 is observed also in neuroblastoma lines expressing other fALS-SOD1s (G37R, G85R, and I113T) cocultured with glioblastoma lines expressing the corresponding mutant enzymes. These effects are consequent to activation of inflammatory processes in G93A-glioblastoma cells stimulated by cocultured G93A-neuroblastoma. Furthermore, selective death of embryonal spinal motor neurons from G93A-SOD1 transgenic mice is induced by coculture with G93A-glioblastoma and prevented by inhibition of NO synthase. Proinflammatory cytokines, interferon-gamma, and nitric oxide are among the molecular signals exchanged between glial and neuronal cells that generate a functional interplay between the two cell types. This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of the disease, where markers of increased oxidative stress and of glial activation have been found.
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PMID:Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells. 1520 63

The equine interleukin-18 (IL-18) cDNA that contains the coding sequence was cloned and a recombinant baculovirus, named AcEIL-18, was constructed. The recombinant protein of the equine IL-18 was expressed by AcEIL-18 and its expression was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Insect cells infected with AcEIL-18 secreted a precursor IL-18 with 24 kilo dalton (kDa) into the culture supernatant. Western blot analysis showed that mature equine IL-18 about 18 kDa was also confirmed without co-expression of caspase-1. Culture supernatant from AcEIL-18 infected cells showed a synergistic effect with recombinant human interleukin-12 for induction of interferon-gamma gene expression in equine peripheral mononuclear cells, indicating that the recombinant equine IL-18 expressed in this study also has biological activity without any treatment.
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PMID:Expression of equine interleukin-18 by baculovirus expression system and its biologic activity. 1521 21

Using in silico methods for screening the human genome for new caspase recruitment domain (CARD) proteins, we have identified INCA (Inhibitory CARD) as a protein that shares 81% identity with the prodomain of caspase-1. The INCA gene is located on chromosome 11q22 between the genes of COP/Pseudo-ICE and ICEBERG, two other CARD proteins that arose from caspase-1 gene duplications. We show that INCA mRNA is expressed in many tissues. INCA is specifically upregulated by interferon-gamma in the monocytic cell lines THP-1 and U937. INCA physically interacts with procaspase-1 and blocks the release of mature IL-1beta from LPS-stimulated macrophages. Unlike COP/Pseudo-ICE and procaspase-1, INCA does not interact with RIP2 and does not induce NF-kappaB activation. Our data show that INCA is a novel intracellular regulator of procaspase-1 activation, involved in the regulation of pro-IL-1beta processing and its release during inflammation.
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PMID:INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. 1538 41

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.
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PMID:Modulation of the inflammatory process by statins. 1582 62

Caspase-1, a cysteine protease is primarily involved in proteolytic activation of proinflammatory cytokines such as interleukin-1beta. It is also involved in some forms of apoptosis. Here we have analyzed the role of p73, a homolog of tumor suppressor p53, in regulating human caspase-1 gene transcription. The caspase-1 promoter was strongly activated by p73alpha and p73beta primarily through a p53/p73 responsive site. Overexpression of p73 by transient transfection increased the caspase-1 mRNA level. Treatment of cells with cisplatin (which increases p73 protein level) resulted in increased caspase-1 promoter activity and its mRNA level. Blocking of p73 function by a dominant negative mutant reduced basal as well as cisplatin-induced caspase-1 promoter activity. Mutation of the p73 responsive site abolished cisplatin-induced activation of the promoter. Interferon-gamma induced caspase-1 promoter activity and this was reduced by p73-directed small hairpin RNA and also by a dominant negative mutant of p73. Abrogation of the p73 responsive site partially inhibited interferon-gamma-induced activation of the caspase-1 promoter. Treatment of HeLa cells with interferon-gamma resulted in an increase in p73 protein as well as its activity. Mutation of the IRF-1 binding site abolished interferon-gamma-induced caspase-1 promoter activity but p73-induced activation was only marginally reduced. IRF-1 cooperated with p73 and cisplatin cooperated with interferon-gamma in the activation of the caspase-1 promoter. Our results show that p73 is a regulator of caspase-1 gene transcription, and is required for optimal activation of the caspase-1 promoter by interferon-gamma.
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PMID:Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin. 1613 20

Elite populations of farm animals under genetic selection are often maintained in high hygiene conditions, yet the commercial populations may be raised in, and are expected to perform well in, environments of varied hygiene levels. This presents special challenges to genetically improve those traits for which genotype by environment interactions are important. Twelve immune-related genes were studied for associations with general mortality and other performance traits in 3 elite commercial broiler chicken lines raised in high and low hygiene environments. The genes were toll-like receptor 4, MD-2 (accessory' protein of TLR4), interferon-gamma, transforming growth factor-beta3, inducible nitric oxide synthase, macrophage migration inhibitory factor, interleukin-2, caspase-1, inhibitor of apoptosis protein-1, tumor necrosis factor-related apoptosis-inducing ligand, chicken B-cell marker, and bone morphogenetic protein-7. From a total of 56 identified single-nucleotide polymorphisms (SNP) in 12 genes, 14 SNP that had moderate allelic frequencies in at least 2 of the 3 lines were typed in about 100 progeny-tested sires from each of 3 elite commercial broiler chicken lines using restriction fragment length polymorphism techniques and then used in association analysis. The traits measured on the progeny (total progeny = 145,467) were: mortality from hatching to 14 d and from 14 to 40 d of age, BW at 7 and 40 d of age, feed conversion, ultrasound breast depth, percentage of breast, eviscerated carcass weight, twisted legs or evident tibial dyschondroplasia, x-ray-inspection-based subclinical or incipient development of tibial dyschondroplasia, curly or crooked toes or bowed legs, oxygen content of blood, and female's antibody titer to infectious bursal disease virus at 27 wk. Association analyses were conducted with allele and haplotype substitution effect models using progeny mean data adjusted for fixed and mate effects as sire trait records. Ten of the 12 genes had SNP associations with at least 1 trait. Most detected effects were with mortality and growth traits. Most gene-SNP trait associations varied by genetic line or with environment. These results indicate that associations of candidate genes with important broiler traits can be identified in multiple environments, and they offer a potential for the implementation of marker-assisted selection for traits expressed in the environment in which the commercial broiler needs to perform. The effects of these immune-related candidate genes, however, are complex and affected by genetic background and environment.
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PMID:Association of twelve immune-related genes with performance of three broiler lines in two different hygiene environments. 1697 41


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