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)

Anecdoctal evidence accumulated over almost 20 years has shown that many different cell types are killed by sustained exposure to high concentrations of extracellular ATP. The plasma membrane receptors involved have been pharmacologically characterized and cloned during the last 3 years, and named purinergic P2X. P2X receptors share an intriguing structural relatedness with Caenorhabditis elegans degenerins and mammalian amiloride-sensitive Na channels (ENaCs). Depending on the ATP dose, length of stimulation and receptor subtype, P2X receptor stimulation may cause necrosis or apoptosis. The intracellular pathways activated are poorly known, but the perturbation in intracellular ion homeostasis clearly plays a major role. ICE proteases (caspases) are also triggered, nonetheless their activation is not requested for ATP-dependent cell death. The physiological meaning of P2X receptor-dependent cytotoxicity is not understood, but an involvement in immune-mediated reactions is postulated.
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PMID:Cytolytic P2X purinoceptors. 1020 Apr 64

Myeloic cells express a peculiar surface receptor for extracellular ATP, called the P2Z/P2X7 purinoreceptor, which is involved in cell death signalling. Here, we investigated the role of caspases, a family of proteases implicated in apoptosis and the cytokine secretion. We observed that extracellular ATP induced the activation of multiple caspases including caspase-1, -3 and -8, and subsequent cleavage of the caspase substrates PARP and lamin B. Using caspase inhibitors, it was found that caspases were specifically involved in ATP-induced apoptotic damage such as chromatin condensation and DNA fragmentation. In contrast, inhibition of caspases only marginally affected necrotic alterations and cell death proceeded normally whether or not nuclear damage was blocked. Our results therefore suggest that the activation of caspases by the P2Z receptor is required for apoptotic but not necrotic alterations of ATP-induced cell death.
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PMID:P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death. 1021 85

The P2X(7) receptor (P2X(7)R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1 beta post-translational processing, we have generated a P2X(7)R-deficient mouse line. P2X(7)R(-/-) macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1 beta comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1 beta produced by the P2X(7)R(-/-) cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1 beta from P2X(7)R(-/-) macrophages. In response to in vivo lipopolysaccharide injection, both wild-type and P2X(7)R(-/-) animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATP-treated, LPS-primed P2X(7)R(-/-) animals. Absence of the P2X(7)R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency, in vivo cytokine signaling cascades are impaired in P2X(7)R-deficient animals. Together these results demonstrate that P2X(7)R activation can provide a signal that leads to maturation and release of IL-1 beta and initiation of a cytokine cascade.
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PMID:Altered cytokine production in mice lacking P2X(7) receptors. 1101 35

Interleukin (IL)-1beta and IL-18 are structurally similar proteins that require caspase-1 processing for activation. Both proteins are released from the cytosol by unknown pathway(s). To better characterize the release pathway(s) for IL-1beta and IL-18 we evaluated the role of lipopolysaccharide priming, of interleukin-1beta-converting enzyme (ICE) inhibition, of human purinergic receptor (P2X(7)) function, and of signaling pathways in human monocytes induced by ATP. Monocytes rapidly processed and released both IL-1beta and IL-18 after exogenous ATP. Despite its constitutive cytosolic presence, IL-18 required lipopolysaccharide priming for the ATP-induced release. Neither IL-1beta nor IL-18 release was prevented by ICE inhibition, and IL-18 release was not induced by ICE activation itself. Release of both cytokines was blocked completely by a P2X7 receptor antagonist, oxidized ATP, and partially by an antibody to P2X(7) receptor. In evaluating the signaling components involved in the ATP effect, we identified that the protein-tyrosine kinase inhibitor, AG126, produced a profound inhibition of both ICE activation as well as release of IL-1beta/IL-18. Taken together, these results suggest that, although synthesis of IL-1beta and IL-18 differ, ATP-mediated release of both cytokines requires a priming step but not proteolytically functional caspase-1.
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PMID:ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. 1105 57

The release of IL-1 beta is a tightly controlled process that requires induced synthesis of the precursor pro-IL-1 beta and a second stimulus that initiates cleavage and secretion of mature IL-1 beta. Although ATP as a second stimulus potently promotes IL-1 beta maturation and release via P2X(7) receptor activation, millimolar ATP concentrations are needed. The human cathelicidin-derived peptide LL37 is a potent antimicrobial peptide produced predominantly by neutrophils and epithelial cells. In this study, we report that LL37 stimulation of LPS-primed monocytes leads to maturation and release of IL-1 beta via the P2X(7) receptor. LL37 induces a transient release of ATP, membrane permeability, caspase-1 activation, and IL-1 beta release without cell cytotoxicity. IL-1 beta release and cell permeability are suppressed by pretreatment with the P2X(7) inhibitors oxidized ATP, KN04, and KN62. In the presence of apyrase, which hydrolyzes ATP to AMP, the effect of LL37 was not altered, indicating that LL37 rather than autocrine ATP is responsible for the activation of the P2X(7) receptor. We conclude that endogenous LL37 may promote IL-1 beta processing and release via direct activation of P2X(7) receptors.
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PMID:A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. 1506 80

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

Interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Here, we examined the role of IL-1 in arterial neointima formation. Carotid artery neointima was induced by ligation, and arteries were harvested 4 weeks after injury. The neointima/media of mice deficient in the IL-1 signaling receptor (IL-1R1(-/-)) was significantly reduced compared to IL-1R1(+/+) controls (P < 0.01). IL-1R1(+/+) mice receiving subcutaneous IL-1ra also had significantly reduced neointima/media compared with placebo (P < 0.05). IL-1beta(-/-) mice had reduced neointima/media compared to wild-type (P < 0.05), whereas IL-1alpha(-/-) mice were no different from controls. Mice deficient in the P2X(7) receptor (involved in IL-1 release) or caspase-1 (involved in IL-1 activation) did not differ in their response to carotid ligation compared to controls. To examine the site of IL-1 signaling, we generated chimeric mice. IL-1R1(+/+) mice receiving IL-1R1(-/-) marrow and IL-1R1(-/-) mice receiving IL-1R1(+/+) marrow both had significantly reduced neointima/media compared with IL-1R1(+/+) to IL-1R1(+/+) (P < 0.05) but had significantly greater neointima/media than IL-1R1(-/-) to IL-1R1(-/-) controls (P < 0.05). These data confirm the importance of IL-1beta signaling in mediating arterial neointima formation and suggest the involvement of IL-1 signaling in both circulating and arterial wall cells. Furthermore, receptor antagonism may be a better therapeutic target than interruption of IL-1beta processing or release.
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PMID:Interleukin-1beta and signaling of interleukin-1 in vascular wall and circulating cells modulates the extent of neointima formation in mice. 1656 12

P2X(7) receptors are ATP-gated cation channels; their activation in macrophage also leads to rapid opening of a membrane pore permeable to dyes such as ethidium, and to release of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta). It has not been known what this dye-uptake path is, or whether it is involved in downstream signalling to IL-1beta release. Here, we identify pannexin-1, a recently described mammalian protein that functions as a hemichannel when ectopically expressed, as this dye-uptake pathway and show that signalling through pannexin-1 is required for processing of caspase-1 and release of mature IL-1beta induced by P2X(7) receptor activation.
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PMID:Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. 1703 48

Dendritic cells (DCs) are professional antigen-presenting cells that initiate the immune response by activating T lymphocytes. DCs express plasma membrane receptors for extracellular nucleotides named P2 receptors (P2Rs). Stimulation of P2Rs in these cells is known to cause chemotaxis, cytokine release, and cell death and to modulate LPS-dependent differentiation. Here we show that stimulation of the P2X(7) receptor subtype (P2X(7)R) causes fast microvesicle shedding from DC plasma membrane. Vesicle release occurs from both immature and mature DCs; however, only vesicles from mature DCs, due to their previous exposure to LPS, contain IL-1beta. Microvesicles, whether from immature or mature DCs, also contain caspase-1 and -3 and cathepsin D. They also express the P2X(7)R in addition to other P2Rs and known markers of immune cells such as major histocompatibility complex II (MHC II) and CD39. Activation of the P2X(7)R by extracellular ATP causes IL-1beta release from the vesicle lumen. Previous studies demonstrated that high extracellular K(+) inhibits IL-1beta processing and release; here we show that high ionic strength reduces microvesicle shedding when compared with a low ionic strength medium but strongly increases microvesicle IL-1beta loading.
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PMID:Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. 1719 99

Genetic factors contribute to inflammatory bowel diseases. Recently, the P2X(7) receptor was found to be a key player in caspase-1-mediated processing of the proinflammatory cytokines, interleukin-1beta and interleukin-18. We therefore aimed to determine whether the gain-of-function single nucleotide polymorphism (SNP) His155Tyr and the loss-of-function SNP Arg307Gln and Glu496Ala were associated with susceptibility to Crohn's disease (CD). For association analysis, 681 unrelated CD patients and 736 healthy controls were enrolled. Furthermore, 490 CD trios were included for segregation analysis. Genotyping was performed by the application of the TaqMan(R) MGB biallelic discrimination system. The Arg307Gln polymorphism revealed a borderline significant difference in genotype frequencies between CD patients and controls (P = 0.06) without implying any pathological significance because of low case numbers. Case-control statistics for the variants His155Tyr and Glu496Ala showed no association with CD phenotype (P = 0.19 and 0.99). Subsequent family-based transmission disequilibrium test did not prove an association of the investigated single-nucleotide polymorphisms with CD. In conclusion, the analysed intragenetic variants of the P2X(7) receptor may not be a susceptibility factor for CD.
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PMID:Functional P2X7 receptor polymorphisms (His155Tyr, Arg307Gln, Glu496Ala) in patients with Crohn's disease. 1725 21


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