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)

The macrophage proinflammatory response to Francisella tularensis (Ft) live vaccine strain (LVS) was shown previously to be TLR2 dependent. The observation that intracellular Ft LVS colocalizes with TLR2 and MyD88 inside macrophages suggested that Ft LVS might signal from within the phagosome. Macrophages infected with LVSDeltaiglC, a Ft LVS mutant that fails to escape from the phagosome, displayed greatly increased expression of a subset of TLR2-dependent, proinflammatory genes (e.g., Tnf) but decreased expression of others (e.g., Ifnb1). This latter subset was similarly mitigated in IFN-beta(-/-) macrophages indicating that while Ft LVS-induced TLR2 signaling is necessary, cytosolic sensing of Ft to induce IFN-beta is required for full induction of the macrophage proinflammatory response. Although LVSDeltaiglC greatly increased IL-1beta mRNA in wild-type macrophages, protein secretion was not observed. IL-1beta secretion was also diminished in Ft LVS-infected IFN-beta(-/-) macrophages. rIFN-beta failed to restore IL-1beta secretion in LVSDeltaiglC-infected macrophages, suggesting that signals in addition to IFN-beta are required for assembly of the inflammasome and activation of caspase-1. IFN-beta plays a central role in controlling the macrophage bacterial burden: bacterial recovery was greater in IFN-beta(-/-) than in wild-type macrophages and treatment of Ft LVS-infected macrophages with rIFN-beta or 5,6-dimethylxanthenone-4-acetic acid, a potent IFN-beta inducer, greatly decreased the intracellular Ft LVS burden. In toto, these observations support the hypothesis that the host inflammatory response to Ft LVS is complex and requires engagement of multiple signaling pathways downstream of TLR2 including production of IFN-beta via an unknown cytosolic sensor and activation of the inflammasome.
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PMID:Macrophage proinflammatory response to Francisella tularensis live vaccine strain requires coordination of multiple signaling pathways. 1845 9

Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1beta accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1beta expression in response to BA spores is required for anti-BA host defenses. Caspase-1(-/-) and IL-1beta(-/-) mice are more susceptible than wild-type (WT) mice to lethal BA infection, are less able to kill BA both in vivo and in vitro, and addition of rIL-1beta to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1beta and nitric oxide, by which BA are killed in WT but not in caspase-1(-/-) mice, suggesting that the spore itself stimulated inflammatory responses. While spores induced IL-1beta in LT-susceptible and -resistant macrophages, LT induced IL-1beta only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1beta. While both spores and LT induced caspase-1 activity and IL-1beta, LT did not induce IL-1beta mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1beta by distinct signaling pathways. Whereas the spore-induced IL-1beta limits BA infection, LT-induced IL-1beta enables BA to escape host defenses.
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PMID:Bacillus anthracis spores and lethal toxin induce IL-1beta via functionally distinct signaling pathways. 1849 80

Research into the five Toll/IL1 receptor (TIR) adaptor proteins involved in innate immunity continues to advance. Here we outline some of the more recent findings. MyD88 has a key role in signalling by the IL1 receptor complex and TLRs. However, a MyD88-independent pathway of IL1beta signalling in neurons has been described which involves the protein kinase Akt, and which has an anti-apoptotic effect. This pathway may also be important for the mechanism whereby Alum exerts its adjuvant effect since this depends on IL1beta but is MyD88-independent. MyD88 is also involved in tumourigenesis in models of hepatocarcinoma and familial associated polyposis (FAP); negative regulation of TLR3 signalling and in PKCepsilon activation. The adaptor Mal is regulated by phosphorylation and caspase-1 cleavage. A variant form of Mal in humans termed S180L confers protection in multiple infectious diseases. TRAM is controlled by myristoylation and phosphorylation and the localisation of TRAM with TLR4 to endosomes is required for activation of IRF3 and induction of IFNbeta. Finally SARM has been shown to regulate TRIF and also appears to be involved in neuronal injury mediated by oxidative stress in mouse neurons. These advances confirm the importance for the TIR domain-containing adapters in host defence and inflammation.
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PMID:Signalling adaptors used by Toll-like receptors: an update. 1870 31

The mammalian target of rapamycin (mTOR) can be viewed as cellular master complex scoring cellular vitality and stress. Whether mTOR controls also innate immune-defenses is currently unknown. Here we demonstrate that TLR activate mTOR via phosphoinositide 3-kinase/Akt. mTOR physically associates with the MyD88 scaffold protein to allow activation of interferon regulatory factor-5 and interferon regulatory factor-7, known as master transcription factors for pro-inflammatory cytokine- and type I IFN-genes. Unexpectedly, inactivation of mTOR did not prevent but increased lethality of endotoxin-mediated shock, which correlated with increased levels of IL-1beta. Mechanistically, mTOR suppresses caspase-1 activation, thus inhibits release of bioactive IL-1beta. We have identified mTOR as indispensable component of PRR signal pathways, which orchestrates the defense program of innate immune cells.
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PMID:Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. 1892 32

IL-4 and IL-13 are instrumental in the development and progression of allergy and atopic disease. Basophils represent a key source of these cytokines and produce IL-4 and IL-13 when stimulated with IL-18, a member of the IL-1 family of cytokines. Comparative analyses of the effects of caspase-1-dependent IL-1 family cytokines on basophil IL-4 and IL-13 production have not been performed, and the signaling pathway proteins required for FcepsilonRI-independent Th2 cytokine production from basophils remain incompletely defined. Using mouse bone marrow-derived cultured basophils, we found that IL-4 and IL-13 are produced in response to IL-18 or IL-33 stimulation. IL-18- or IL-33-mediated Th2 cytokine production is dependent on MyD88 and p38alpha signaling proteins. In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils.
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PMID:IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. 1979 2

Some fungal species are opportunistic pathogens that can cause infection in people with compromised immune systems. Activation of caspase-1 and the subsequent secretion of mature interleukin (IL)-1beta is a major signaling pathway of the innate immune system, but how yeasts induce caspase-1 activation is unknown. We show here that stimulation of macrophages and dendritic cells with heat-killed Saccharomyces cerevisiae or the purified cell wall components zymosan and mannan induced caspase-1 activation and IL-1beta secretion when combined with ATP. Macrophages deficient for the inflammasome adaptor ASC were defective in caspase-1 activation and IL-1beta secretion, suggesting involvement of an ASC-dependent inflammasome. Indeed, caspase-1 activation was abrogated in macrophages lacking the NOD-like (NLR) protein Cryopyrin/Nalp3 and in wild type macrophages pretreated with the pannexin-1 inhibitor probenecid. IL-1beta secretion further required the Toll-like receptor (TLR) adaptors MyD88 and TRIF, and partially relied on TLR2. We previously showed that bacterial molecules such as lipopolysaccharide (LPS) and peptidoglycan induce activation of caspase-7 through the Cryopyrin inflammasome. Similarly, Cryopyrin and ASC were required for activation of caspase-7 in macrophages stimulated with zymosan or mannan and ATP. These results demonstrate that the conserved fungal components zymosan and mannan require ASC and Cryopyrin for caspase-1 activation and IL-1beta secretion and suggest an important role for the Cryopyrin inflammasome during fungal infections.
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PMID:Fungal zymosan and mannan activate the cryopyrin inflammasome. 1950 80

The Nlrp3 inflammasome is critical for the activation of caspase-1 in response to danger signals and particulate matter. However, its role in sterile inflammation remains unclear because prestimulation of phagocytic cells with microbial molecules is required for caspase-1 activation. We show here that exposure of macrophages and dendritic cells to TNF-alpha promotes ATP- or silica-mediated caspase-1 activation and IL-1beta secretion in the absence of microbial stimulation. The effect of TNF-alpha was abolished in macrophages deficient in TNF receptor I and II, Nlrp3, or ASC, whereas that induced by TLR ligands required MyD88/Trif. In addition to TNF-alpha, IL-1alpha and IL-1beta promoted caspase-1 activation via Nlrp3 in response to ATP. Remarkably, macrophages tolerized to TNF-alpha, but not to LPS, retained full sensitivity to ATP stimulation via Nlrp3. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the Nlrp3 inflammasome in the absence of microbial infection.
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PMID:Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. 1954 72

Modified vaccinia virus Ankara (MVA) is an attenuated double-stranded DNA poxvirus currently developed as a vaccine vector against HIV/AIDS. Profiling of the innate immune responses induced by MVA is essential for the design of vaccine vectors and for anticipating potential adverse interactions between naturally acquired and vaccine-induced immune responses. Here we report on innate immune sensing of MVA and cytokine responses in human THP-1 cells, primary human macrophages and mouse bone marrow-derived macrophages (BMDMs). The innate immune responses elicited by MVA in human macrophages were characterized by a robust chemokine production and a fairly weak pro-inflammatory cytokine response. Analyses of the cytokine production profile of macrophages isolated from knockout mice deficient in Toll-like receptors (TLRs) or in the adapter molecules MyD88 and TRIF revealed a critical role for TLR2, TLR6 and MyD88 in the production of IFNbeta-independent chemokines. MVA induced a marked up-regulation of the expression of RIG-I like receptors (RLR) and the IPS-1 adapter (also known as Cardif, MAVS or VISA). Reduced expression of RIG-I, MDA-5 and IPS-1 by shRNAs indicated that sensing of MVA by RLR and production of IFNbeta and IFNbeta-dependent chemokines was controlled by the MDA-5 and IPS-1 pathway in the macrophage. Crosstalk between TLR2-MyD88 and the NALP3 inflammasome was essential for expression and processing of IL-1beta. Transcription of the Il1b gene was markedly impaired in TLR2(-/-) and MyD88(-/-) BMDM, whereas mature and secreted IL-1beta was massively reduced in NALP3(-/-) BMDMs or in human THP-1 macrophages with reduced expression of NALP3, ASC or caspase-1 by shRNAs. Innate immune sensing of MVA and production of chemokines, IFNbeta and IL-1beta by macrophages is mediated by the TLR2-TLR6-MyD88, MDA-5-IPS-1 and NALP3 inflammasome pathways. Delineation of the host response induced by MVA is critical for improving our understanding of poxvirus antiviral escape mechanisms and for designing new MVA vaccine vectors with improved immunogenicity.
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PMID:Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. 1954 80

The mechanism by which bacterial pathogens activate caspase-1 via Nlrp3 remains poorly understood. In this study, we show that the ability of Staphylococcus aureus, a leading cause of infection in humans, to activate caspase-1 and induce IL-1beta secretion resides in culture supernatants of growing bacteria. Caspase-1 activation induced by S. aureus required alpha-, beta-, and gamma-hemolysins and the host Nlrp3 inflammasome. Mechanistically, alpha- and beta-hemolysins alone did not trigger caspase-1 activation, but they did so in the presence of bacterial lipoproteins released by S. aureus. Notably, caspase-1 activation induced by S. aureus supernatant was independent of the P2X7 receptor and the essential TLR adaptors MyD88 and TIR domain-containing adapter-inducing IFN-beta, but was inhibited by extracellular K(+). These results indicate that S. aureus hemolysins circumvent the requirement of ATP and the P2X7 receptor to induce caspase-1 activation via Nlrp3. Furthermore, these studies revealed that hemolysins promote in the presence of lipoproteins the activation of the Nlrp3 inflammasome.
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PMID:A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. 1971 10

The role of proinflammatory cytokine production in the pathogenesis of malaria is well established, but the identification of the parasite products that initiate inflammation is not complete. Hemozoin is a crystalline metabolite of hemoglobin digestion that is released during malaria infection. In the present study, we characterized the immunostimulatory activity of pure synthetic hemozoin (sHz) in vitro and in vivo. Stimulation of naive murine macrophages with sHz results in the MyD88-independent activation of NF-kappaB and ERK, as well as the release of the chemokine MCP-1; these responses are augmented by IFN-gamma. In macrophages prestimulated with IFN-gamma, sHz also results in a MyD88-dependent release of TNF-alpha. Endothelial cells, which encounter hemozoin after schizont rupture, respond to sHz by releasing IL-6 and the chemokines MCP-1 and IL-8. In vivo, the introduction of sHz into the peritoneal cavity produces an inflammatory response characterized by neutrophil recruitment and the production of MCP-1, KC, IL-6, IL-1alpha, and IL-1beta. MCP-1 and KC are produced independently of MyD88, TLR2/4 and TLR9, and components of the inflammasome; however, neutrophil recruitment, the localized production of IL-1beta, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway, and the inflammasome components ICE (IL-1beta-converting enzyme), ASC (apoptosis-associated, speck-like protein containing CARD), and NALP3. Of note, inflammasome activation by sHz is reduced by allopurinol, which is an inhibitor of uric acid synthesis. These data suggest that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 inflammasome.
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PMID:Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid. 1978 73


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