Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the molecular mechanisms of cell death induced by 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), a potent inhibitor of RNA synthesis, using mouse mammary tumor FM3A cells and human fibrosarcoma HT1080 cells. ECyd induced the characteristics of apoptosis on these cells, such as morphological changes, DNA fragmentations and caspase-3-like protease activation. General caspases inhibitor, Z-Asp-CH2-DCB inhibited cell death. Interestingly, we also found that ECyd induced rRNA fragmentation. The cleavage pattern of rRNA resembled in that mediated by RNase L. On the other hands, it was suggested that caspase-1, 3, 8 and 9 concerned with ECyd-induced apoptosis through mitochondria. ECyd-induced rRNA fragmentation was inhibited by general caspases inhibitor (Z-Asp-CH2-DCB) and caspase-5 inhibitor (Z-WEHD-fmk). So it is clear that caspase-5 (ICErel III/TY), member of ICE (Interleukin-1 beta-converting enzyme) protease, activated pathway concerned with ECyd-induced rRNA fragmentation. These results indicate that antitumor mechanisms of ECyd are involved in caspase-dependent activation of RNase L. rRNA fragmentation may occur one of the death events, as a result of inhibition of RNA synthesis and play an important role in the antitumor activity of ECyd.
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PMID:Anticancer mechanisms of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd, TAS-106). 1290 95

Dendritic cells provide a critical link between innate and acquired immunity. In this study, we demonstrate that the bacterial pathogen Salmonella enterica serovar Typhimurium can efficiently kill these professional phagocytes via a mechanism that is dependent on sipB and the Salmonella pathogenicity island 1-encoded type III protein secretion system. Rapid phosphatidylserine redistribution, caspase activation, and loss of plasma membrane integrity were characteristic of dendritic cells infected with wild-type Salmonella, but not sipB mutant bacteria. Caspase-1 was particularly important in this process because Salmonella-induced dendritic cell death was dramatically reduced in the presence of a caspase-1-specific inhibitor. Furthermore, dendritic cells obtained from caspase-1-deficient mice, but not heterozygous littermate control mice, were resistant to Salmonella-induced cytotoxicity. We hypothesize that Salmonella have evolved the ability to selectively kill professional APCs to combat, exploit, or evade immune defense mechanisms.
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PMID:Salmonella rapidly kill dendritic cells via a caspase-1-dependent mechanism. 1466 78

Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-1beta into the active cytokine mature IL-1beta. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3,it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-1 in cell death has been questioned, and not definitively demonstrated. Furthermore, if caspase-1 does play a role in cell death, its position in the apoptotic hierarchy has not been clearly defined. Previous studies have shown that caspase-1 knockout (KO) mice and transgenic mice expressing a dominant-negative caspase-1 construct are resistant to ischemic brain injury. We provide direct evidence that caspase-1 plays a key role in neuronal cell death and that caspase-1 is an apical activator of the cell death pathway in the premitochondrial collapse stage. Furthermore, we demonstrate that Rip2/Cardiak/Rick is a stress-inducible upstream modulator of pro-caspase-1 apoptotic activation. We provide evidence that Bid cleavage appears to be an important downstream effector of caspase-1-mediated cell death. Our data demonstrate that caspase-1 is an apical mediator of neuronal cell death during in vitro hypoxia, and confirmed in vivo in ischemia, and provide insights into the sequence of events involved in this pathological cell death process.
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PMID:Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. 1466 41

Caspase-1/interleukin-1beta (IL-1beta)-converting enzyme (ICE) cleaves IL-1beta and IL-18 precursor proteins to the active forms of these proinflammatory cytokines. Since both cytokines are constitutively expressed in the brain, we investigated whether this is also the case for caspase-1. Using an antibody raised against the p10-subunit of the active enzyme, constitutive expression of caspase-1 immunoreactivity was found in nerve cells in the arcuate nucleus and in nerve fibres throughout the brain. Co-localisation with alpha-melanocyte stimulating hormone was demonstrated. The distribution pattern of caspase-1 immunoreactive structures is consistent with a role to produce mature IL-1beta in regions where IL-1beta mediates fever and sleep.
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PMID:Neuronal expression of caspase-1 immunoreactivity in the rat central nervous system. 1469 52

Caspase-1 [IL-1beta-converting enzyme (ICE)] processes substrate precursor molecules to yield the biologically active form of IL-1beta and IL-18, both of which are considered to play important roles in the host defense by activation of both innate and adaptive immunity. We evaluated the immune response of caspase-1(-/-) mice to Listeria monocytogenes (LM) infection. LM eradication in the early phase of infection was impaired in the mutant mice with a prominent decrease in IL-18 and IFN-gamma production, but not in IL-12. Caspase-1(-/-) spleen cells including dendritic cells and NK cells produced less IFN-gamma in response to heat-killed LM than wild-type cells in vitro. IFN-gamma production and bactericidal activity in LM-infected caspase-1(-/-) mice was reconstituted to normal levels by adding back IL-18 at the initial phase of infection, suggesting that the lack of this cytokine is primarily responsible for the susceptibility of caspase-1(-/-) mice against LM infection. Moreover, IFN-gamma injection of caspase-1(-/-) mice corrected the deficiency in pathogen clearance. In contrast, LM-specific acquired immunity in caspase-1(-/-) mice was normal and they successfully cleared the pathogen following secondary infection, in spite of a moderate skewing of cytokine profile to T(h)2 when compared to wild-type mice. These data shed light on the importance of caspase-1-mediated IL-18 processing in innate immunity against facultative intracellular pathogens.
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PMID:Roles of caspase-1 in Listeria infection in mice. 1473 19

A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
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PMID:The design and synthesis of sulfonamides as caspase-1 inhibitors. 1474 Dec 95

The mechanisms underlying caspase-1 activation and IL-1beta processing during inflammatory activation of monocytes and macrophages are not well defined. Here, we describe an in vitro proteolytic processing assay that allows for comparison of caspase-1 regulatory components in a cell-free system separately from the confounding issue of IL-1beta secretion. Analysis of in vitro IL-1beta and caspase-1 processing in lysates from unstimulated Bac1 murine macrophages indicated a slow rate of basal caspase-1 activation and proteolytic maturation of IL-1beta. In contrast, brief (5 min) treatment of intact macrophages with extracellular ATP (as an activator of the P2X(7) receptor) or nigericin before cell lysis markedly accelerated the in vitro processing of caspase-1 and IL-1beta. This acceleration of in vitro processing was strictly dependent on loss of intracellular K(+) from the intact cells. The induction of in vitro caspase-1 activation by lysis per se or by K(+) loss before lysis was sensitive to pretreatment of intact macrophages with the tyrphostin AG-126 or bromoenol lactone, an inhibitor of Ca(2+)-independent phospholipase A(2). Caspase-1 activation and IL-1beta processing in lysates from unstimulated macrophages were also accelerated by addition of recombinant ASC, a previously identified adapter protein that directly associates with caspase-1. These data indicate that increased K(+) efflux via P2X(7) nucleotide receptor stimulation activates AG-126- and bromoenol lactone-sensitive signaling pathways in murine macrophages that result in stably maintained signals for caspase-1 regulation in cell-free assays.
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PMID:Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. 1507 9

Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, respectively. The adaptors ASC, Ipaf and RIP2 have each been proposed to regulate caspase-1 (also called interleukin (IL)-1 converting enzyme), which is activated within the 'inflammasome', a complex comprising several adaptors. Here we show the impact of ASC-, Ipaf- or RIP2-deficiency on inflammasome function. ASC was essential for extracellular ATP-driven activation of caspase-1 in toll-like receptor (TLR)-stimulated macrophages. Accordingly, ASC-deficient macrophages exhibited defective maturation of IL-1beta and IL-18, and ASC-null mice were resistant to lipopolysaccharide-induced endotoxic shock. Furthermore, activation of caspase-1 in response to an intracellular pathogen (Salmonella typhimurium) was abrogated severely in ASC-null macrophages. Unexpectedly, Ipaf-deficient macrophages activated caspase-1 in response to TLR plus ATP stimulation but not S. typhimurium. Caspase-1 activation was not compromised by loss of RIP2. These data show that whereas ASC is key to caspase-1 activation within the inflammasome, Ipaf provides a special conduit to the inflammasome for signals triggered by intracellular pathogens. Notably, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways.
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PMID:Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. 1519 Feb 55

The release of IL-1beta as an active, mature cytokine requires proteolytic processing by caspase-1, which is recruited to signaling complexes that facilitate its autocatalytic proteolysis and activation. Caspase-1 processing has been characterized in human monocyte and murine macrophage model systems, and comparative analyses indicate significant mechanistic differences in caspase-1 activation by these cell types. In this study, we used an in vitro processing assay to compare caspase-1 activation in THP-1 human monocytes vs. Bac1.2F5 murine macrophages. These in vitro caspase-1 and IL-1beta processing reactions indicated a higher rate of constitutive caspase-1 activation in lysates from THP-1 vs. Bac1 cells. Transfer of small amounts of THP-1 lysate to Bac1 lysate rapidly increased in vitro procaspase-1 and proIL-1beta processing in the latter preparation. The transferable activation factor(s) was heat-labile, > or =10 kDa, and unaffected by immunodepletion of procaspase-1 from the THP-1 lysate. This transactivating effect of THP-1 lysate on processing in Bac1 lysates could be mimicked by addition of purified recombinant human caspase-1. The constitutive caspase-1 and IL-1beta processing reactions in THP-1 lysates were insensitive to pharmacological blockade by the tyrphostin, AG126, and the phospholipase A2 inhibitor bromoenol lactone (BEL); contrarily, the same processing reactions were inhibited in lysates from Bac1 cells pretreated with either AG126 or BEL. These observations indicate significant biochemical differences in the assembly and regulation of caspase-1 signaling complexes within human monocyte and murine macrophage models of inflammatory activation. These differences need to be considered when comparing or pharmacologically manipulating IL-1beta processing and release in various model systems.
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PMID:Differing caspase-1 activation states in monocyte versus macrophage models of IL-1beta processing and release. 1524 Jul 53

Epidemiological studies have identified abuse of nitrite inhalants as an independent co-factor in HIV infection and in Kaposi's sarcoma (KS) in AIDS patients. In the present study we investigated the ability of macrophages from mice exposed to isobutyl nitrite to produce the inflammatory cytokine IL-1beta, upon stimulation with IFN-gamma and LPS. The production of IL-1beta was inhibited up to 55%. IL-1beta mRNA transcription was reduced by 35% following nitrite inhalant exposure, consistent with inhibition of activation-induced phosphorylation of macrophage mitogen-activated protein kinase p38. However, synthesis of the 31 kDa IL-1beta precursor protein was only marginally inhibited. Caspase-1, which cleaves the precursor IL-1beta into mature 17 kDa IL-1beta, was examined. Nitrite inhalant exposure blocked activation-induced increases in caspase-1 activity, consistent with a 50% reduction in 17 kDa IL-1beta shown in Western blots. Thus, exposure to nitrite inhalants reduced macrophage production of IL-1beta by reducing transcription, as well as post-translational processing mediated by caspase-1.
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PMID:Production of macrophage IL-1beta was inhibited both at the levels of transcription and maturation by caspase-1 following inhalation exposure to isobutyl nitrite. 1529 46


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