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)

CDC are exotoxins secreted by many Gram-positive bacteria that bind cholesterol and oligomerize to form pores in eukaryotic cell membranes. We demonstrate that CDC TLO induces caspase-1 cleavage and the rapid release of IL-1beta from LPS-primed murine BMDM. IL-1beta secretion depends on functional toxin pore formation, as free cholesterol, which prevents TLO binding to cell membranes, blocks the cytokine release. Secretion of the mature forms of IL-1beta and caspase-1 occurs only at lower TLO doses, whereas at a higher concentration, cells release the biologically inactive proforms. IL-1beta release at a low TLO dose requires potassium efflux, calcium influx, and the activities of calcium-independent PLA(2), caspase-1, and cathepsin B. Additionally, mature IL-1beta release induced by a low TLO dose is dependent on the NLRP3 inflammasome, and pro-IL-1beta release induced by a high TLO dose occurs independently of NLRP3. These results further elucidate a mechanism of CDC-induced IL-1beta release and suggest a novel, immune evasion strategy in which IL-1beta-containing macrophages might release primarily inactive cytokine following exposure to high doses of these toxins.
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PMID:Cholesterol-dependent cytolysins induce rapid release of mature IL-1beta from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. 1967 7

To understand more about how the body recognizes alum we characterized the early innate and adaptive responses in mice injected with the adjuvant. Within hours of exposure, alum induces a type 2 innate response characterized by an influx of eosinophils, monocytes, neutrophils, DCs, NK cells and NKT cells. In addition, at least 13 cytokines and chemokines are produced within 4 h of injection including IL-1beta and IL-5. Optimal production of some of these, including IL-1beta, depends upon both macrophages and mast cells, whereas production of others, such as IL-5, depends on mast cells only, suggesting that both of these cell types can detect alum. Alum induces eosinophil accumulation partly through the production of mast cell derived IL-5 and histamine. Alum greatly enhances priming of endogenous CD4 and CD8 T cells independently of mast cells, macrophages, and of eosinophils. In addition, Ab levels and Th2 bias was similar in the absence of these cells. We found that the inflammation induced by alum was unchanged in caspase-1-deficient mice, which cannot produce IL-1beta. Furthermore, endogenous CD4 and CD8 T cell responses, Ab responses and the Th2 bias were also not impacted by the absence of caspase-1 or NLRP3. These data suggest that activation of the inflammasome and the type 2 innate response orchestrated by macrophages and mast cells in vivo are not required for adjuvant effect of alum on endogenous T and B cell responses.
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PMID:Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. 1973 27

Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1beta (IL-1beta) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking K(ATP) subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1beta secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome-associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1beta secretion.
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PMID:Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. 1980 29

Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal alpha-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus alpha-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant alpha-hemolysin, we now demonstrate that alpha-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant alpha-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to alpha-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by alpha-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1beta and IL-18. Additionally, alpha-hemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation.
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PMID:Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. 1982 85

Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.
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PMID:Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. 1991 68

The NOD-like receptors (NLRs) are a family of intracellular sensors of microbial motifs and damage-associated signals that have emerged as being a crucial component of the innate immune responses and inflammation. The inflammasome is a multiprotein complex, which include NLRs, their adaptor proteins and pro-caspase-1, that stimulates caspase-1 activation to promote the processing and secretion of proinflammatory cytokines interleukin 1beta (IL-1beta), IL-18 and IL-33, as well as "pyroptosis", a form cell death induced by bacterial pathogens. Among the various inflammasomes, the NLRP3 inflammasome is triggered by diverse set of molecules and signals. Recent reports indicate that infection by certain viruses also results in inflammasome activation. Here, we review our current understanding of the mechanism by which various stimuli activate inflammasomes. Further, we discuss the role of inflammasomes in the induction of adaptive immunity against influenza virus infection.
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PMID:[Inflammasomes in viral infection]. 1992 84

Different NOD-like receptors, including NLRP1, NLRP3, and NLRC4, as well as the recently identified HIN-200 protein, AIM2, form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. Listeria monocytogenes is an intracellular pathogen that is actively phagocytosed by monocytes/macrophages and subsequently escapes from the phagosome into the host cell cytosol, depending on its pore-forming toxin listeriolysin O (LLO). In this study, we demonstrate that human PBMCs produced mature IL-1beta when infected with wild-type L. monocytogenes or when treated with purified LLO. L. monocytogenes mutants lacking LLO or expressing a noncytolytic LLO as well as the avirulent Listeria innocua induced strongly impaired IL-1beta production. RNA interference and inhibitor experiments in human PBMCs as well as experiments in Nlrp3 and Rip2 knockout bone marrow-derived macrophages demonstrated that the Listeria-induced IL-1beta release was dependent on ASC, caspase-1, and NLRP3, whereas NOD2, Rip2, NLRP1, NLRP6, NLRP12, NLRC4, and AIM2 appeared to be dispensable. We found that L. monocytogenes-induced IL-1beta production was largely dependent on phagosomal acidification and cathepsin B release, whereas purified LLO activated an IL-1beta production independently of these mechanisms. Our results indicate that L. monocytogenes-infected human PBMCs produced IL-1beta, largely depending on an LLO-mediated phagosomal rupture and cathepsin B release, which is sensed by Nlrp3. In addition, an LLO-dependent but cathepsin B-independent NLRP3 activation might contribute to some extent to the IL-1beta production in L. monocytogenes-infected cells.
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PMID:Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3. 2000 85

In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases. While defined ligands have been identified for the NLRP1, IPAF, and AIM2 inflammasomes, little is known about the activation mechanisms of the NLRP3 inflammasome. Numerous different molecular entities, such as various crystals, pore-forming toxins, or extracellular ATP can trigger the NLRP3 inflammasome. Recent work proposes that NLRP3 is activated indirectly by host factors that are generated in response to NLRP3 triggers.
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PMID:The inflammasomes: mechanisms of activation and function. 2006 Jun 99

Familial cold-induced autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease make up cryopyrin-associated periodic syndromes (CAPS). These are autoinflammatory inherited disorders caused by autosomal dominant gain-of-function mutations in the NLRP3 gene, located on chromosome 1q44. Cryopyrin/NALP3/NLRP3 is an essential component of intracellular inflammasomes that activate caspase-1, which in turn converts interleukin-1beta (IL-1beta) to its active form. IL-1beta is a potent cytokine that activates diverse elements of the immune and inflammatory systems leading to the pathogenic changes characteristic of CAPS. There is therefore much interest in the development of IL-1beta blocking agents as novel biologic treatments for these conditions. Canakinumab (ACZ-885; Ilaris, Novartis Pharma) is a fully humanized monoclonal antibody (mAb) specific for IL-1beta and is indicated for a wide range of inflammatory disorders including CAPS. This review will assess the utility of canakinumab as a treatment for CAPS.
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PMID:Canakinumab for the treatment of cryopyrin-associated periodic syndromes. 2006 37

By destroying tumor cells, conventional anticancer therapies may stimulate the host immune system to eliminate residual disease. Anthracyclines, oxaliplatin, and ionizing irradiation activate a type of tumor cell death that elicits efficient anticancer immune responses depending on interferon gamma (IFNgamma) and the IFNgamma receptor. Thus, dying tumor cells emit danger signals that are perceived by dendritic cells (DC), which link innate and cognate immune responses. Recently, we observed that ATP was released by tumor cells succumbing to chemotherapy. ATP activates purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and driving the secretion of interleukin-1beta (IL-1beta). IL-1beta then is required for the adequate polarization of IFNgamma-producing CD8(+) T cells. These results imply a novel danger signal, ATP, and a novel receptor, P2RX7, in the chemotherapy-elicited anticancer immune response.
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PMID:Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. 2008 77


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