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)

Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.
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PMID:Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. 1849 30

The multifunctional cytokine interleukin-18 (IL-18) is an important mediator in intestinal inflammatory processes. The aim of this study was to evaluate the constitutive expression of IL-18 and its receptors (IL-18Ralpha and IL-18Rbeta) in intestinal epithelial cells (IEC) stimulated by tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In addition, cellular proliferation and evaluation of brush border enzymes as differentiation markers were studied. Nontransformed rat intestinal epithelial IEC-6 cells were grown on an extracellular matrix (ECM) in medium with or without TNF-alpha, IFN-gamma, or a combination of both. Gene expression of IL-18, its receptors and apoptotic markers was evaluated using real-time PCR. Expression of IL-18Ralpha protein was demonstrated by flow cytometry and Western blot. Enzymatic activities of brush border enzymes and caspase-1 were determined. The constitutive expression of IL-18, IL-18Ralpha and IL-18Rbeta mRNAs and proteins were detected in IEC-6 cells. The biologically active form of IL-18 was released in response to TNF-alpha and IFN-gamma treatment. Exogenous IL-18 had no effect on cellular proliferation, brush border enzyme activities, and gene expression of apoptotic markers. However, the addition of IL-18 stimulated production and release of the chemokine IL-8. These data suggest that IEC-6 cells may be not only a source of IL-18 but also a target for its action.
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PMID:Constitutive expression of IL-18 and IL-18R in differentiated IEC-6 cells: effect of TNF-alpha and IFN-gamma treatment. 1854 59

Oral administration of bovine lactoferrin (bLF) inhibits carcinogenesis in the colon and other organs in rats, and lung metastasis in mice. A likely mechanism by which bLF mediates its anticarcinogenesis effects is by enhanced expression of cytokines and subsequent activation of immune cells. Oral administration of bLF enhances expression of interleukin-18 (IL-18) mRNA in the mucosa of the small intestine of mice. Importantly, the pepsin hydrolysate of bLF (bLFH) also induced expression of IL-18 mRNA in the mouse small intestine and a peptide produced by pepsin digestion of bLF, bovine lactoferricin (bLFcin), induced expression of mature IL-18 in organ culture. In addition to IL-18, bLF and bLFcin both induced significant increases in caspase-1 activity in peritoneal macrophages and in organ cultures. The increase of mature IL-18 by macrophages was inhibited by caspase-1 inhibitor: caspase-1 is known to cleave the proform of IL-18 to produce active mature IL-18. Finally, bLF also induced expression of IFNgamma by peritoneal macrophages. Importantly, in IFNgamma knockout (GKO) mice, bLF administration resulted in increased expression of caspase-1 protein, but induction of IL-18 mRNA, caspase-1 activity, and mature IL-18 was not observed. These results indicate that orally administered bLF can induce expression of IFNgamma and caspase-1 in the small intestine. IFNgamma in turn increases expression of target genes, including IL-18. Active caspase-1 then cleaves pro-IL-18 to generate mature IL-18. Thus, bLF activates an effector pathway mediated by IFNgamma, caspase-1, and IL-18. We also show that ingested bLF is able to activate more than a single effector pathway. For example, in GKO mice while bLF administration could not activate the IFNgamma/caspase-1/IL-18 effector pathway, it was able to inhibit tumor growth and metastasis by activation of an IFNalpha/IL-7 effector pathway.
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PMID:Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine. 1863 43

Multiple microbial components trigger the formation of an inflammasome complex that contains pathogen-specific nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs), caspase-1, and in some cases the scaffolding protein ASC. The NLR protein Nalp1b has been linked to anthrax lethal toxin (LT)-mediated cytolysis of murine macrophages. Here we demonstrate that in unstimulated J774A.1 macrophages, caspase-1 and Nalp1b are membrane associated and part of approximately 200- and approximately 800-kDa complexes, respectively. LT treatment of these cells resulted in caspase-1 recruitment to the Nalp1b-containing complex, concurrent with processing of cytosolic caspase-1 substrates. We further demonstrated that Nalp1b and caspase-1 are able to interact with each other. Intriguingly, both caspase-1 and Nalp1b were membrane associated, while the caspase-1 substrate interleukin-18 was cytosolic. Caspase-1-associated inflammasome components included, besides Nalp1b, proinflammatory caspase-11 and the caspase-1 substrate alpha-enolase. Asc was not part of the Nalp1b inflammasome in LT-treated macrophages. Taken together, our findings suggest that LT triggers the formation of a membrane-associated inflammasome complex in murine macrophages, resulting in cleavage of cytosolic caspase-1 substrates and cell death.
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PMID:Anthrax lethal toxin triggers the formation of a membrane-associated inflammasome complex in murine macrophages. 1912 2

We previously reported in ischemic acute kidney injury (AKI) in mice that caspase-1-mediated production of interleukin-18 (IL-18) is pathogenic and that macrophage depletion by liposome-encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, reversed the functional protection against AKI in both LEC-treated wild-type and caspase-1 -/- mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild-type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice, and IL-18 -/- mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild-type as well as IL-18 BP Tg and IL-18 -/- mice reversed the functional protection against AKI in LEC-treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage-depleted wild-type and caspase-1 -/- mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage-depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.
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PMID:Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice. 1912 55

The gram-negative rod Burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease which is endemic in tropical and subtropical areas. The bacterium multiplies intracellularly within the cytosol, induces the formation of actin tails, and can spread directly from cell to cell. Recently, it has been shown that B. pseudomallei can induce caspase-1-dependent cell death in macrophages. The aim of the present study was to further elucidate the role of caspase-1 during B. pseudomallei infection. In vivo experiments with caspase-1(-/-) mice revealed a high susceptibility to B. pseudomallei challenge. This phenotype was associated with a significantly higher bacterial burden 2 days after infection and decreased gamma interferon (IFN-gamma) and interleukin-18 cytokine levels 24 h after infection compared to control animals. caspase-1(-/-) bone marrow-derived macrophages (BMM) exhibited strong caspase-3 expression and reduced cell damage compared to wild-type (WT) cells during early B. pseudomallei infection, indicating "classical" apoptosis, whereas WT BMM showed signs of rapid caspase-1-dependent cell death. Moreover, we found that caspase-1(-/-) BMM had a strongly increased bacterial burden compared to WT cells 3 h after infection under conditions where no difference in cell death could be observed between both cell populations at this time point. We therefore suggest that caspase-1-dependent rapid cell death might contribute to resistance by reducing the intracellular niche for B. pseudomallei, but, in addition, caspase-1 might also have a role in controlling intracellular replication of B. pseudomallei in macrophages. Moreover, caspase-1-dependent IFN-gamma production is likely to contribute to resistance in murine melioidosis.
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PMID:Caspase-1 mediates resistance in murine melioidosis. 1917 18

Caspase-1 activation is a key feature of the innate immune response of macrophages elicited by pathogens and a variety of toxins. Here, we determined the requirement for different adapter proteins involved in regulating host processes mediated by caspase-1 after macrophage infection by Legionella pneumophila. The adapter protein Asc was found to be important for caspase-1 activation during L. pneumophila infection. Activation of caspase-1 through Asc did not require the flagellin-sensing pathway involving the host nucleotide-binding domain and leucine-rich repeat-containing protein Ipaf (NLRC4). Asc-dependent caspase-1 activation was inhibited by high extracellular potassium levels, whereas Ipaf-dependent activation was unaffected by potassium treatment. Activation of caspase-1 in macrophages occurred independently of Nalp3 and proteasome activity, suggesting that a previously uncharacterized mechanism for caspase-1 activation through Asc may be triggered by L. pneumophila. Rapid pore formation and pyroptosis induced by L. pneumophila required caspase-1, Ipaf, and bacterial flagellin but occurred independently of Asc. Equivalent levels of active interleukin-18 (IL-18) were detected in the lungs of mice infected with a flagellin-deficient strain of L. pneumophila and Asc-deficient mice infected with wild-type L. pneumophila. Active IL-18 was undetectable in the lungs of Asc-deficient mice infected with an L. pneumophila flagellin mutant, indicating independent roles for Ipaf and Asc in caspase-1-mediated processing and release of IL-18 in vivo. Ipaf-dependent activation of caspase-1 restricted bacterial replication in vivo, whereas Asc was dispensable for restriction of L. pneumophila replication in mice. Thus, L. pneumophila-mediated caspase-1 activation involves the coordinate activities of inflammasomes differentially regulated by Ipaf and Asc.
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PMID:Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila. 1923 18

Salmonella enterica serotype Typhimurium causes acute inflammatory diarrhea in humans. Flagella contribute to intestinal inflammation, but the mechanism remains unclear since most mutations abrogating pattern recognition of flagellin also prevent motility and reduce bacterial invasion. To determine the contribution of flagellin pattern recognition to the generation of innate immune responses, we compared in two animal models a nonmotile, but flagellin-expressing and -secreting serotype Typhimurium strain (flgK mutant) to a nonmotile, non-flagellin-expressing strain (flgK fliC fljB mutant). In vitro, caspase-1 can be activated by cytosolic delivery of flagellin, resulting in release of the interferon gamma inducing factor interleukin-18 (IL-18). Experiments with streptomycin-pretreated caspase-1-deficient mice suggested that induction of gamma interferon expression in the murine cecum early (12 h) after serotype Typhimurium infection was caspase-1 dependent but independent of flagellin pattern recognition. In addition, mRNA levels of the CXC chemokines macrophage inflammatory protein 2 and keratinocyte-derived chemokine were markedly increased early after serotype Typhimurium infection of streptomycin-pretreated wild-type mice regardless of flagellin expression. In contrast, in bovine ligated ileal loops, flagellin pattern recognition contributed to increased mRNA levels of macrophage inflammatory protein 3alpha and more fluid accumulation at 2 h after infection. Collectively, our data suggest that pattern recognition of flagellin contributes to early innate host responses in the bovine ileal mucosa but not in the murine cecal mucosa.
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PMID:Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype typhimurium infection. 1923 29

A genomic locus called "region of difference 1" (RD1) in Mycobacterium tuberculosis has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 (DeltaRD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1beta, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and DeltaRD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1beta and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of DeltaRD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages.
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PMID:The RD1 locus in the Mycobacterium tuberculosis genome contributes to activation of caspase-1 via induction of potassium ion efflux in infected macrophages. 1959 75

Interleukin-18 is a proinflammatory, proapoptotic, and proatherogenic cytokine belonging to the interleukin-1 family of cytokines. The cytokine exerts many unique immunologic and biological effects. It is produced as a biologically inactive and leaderless precursor protein, which must be cleaved into its mature form by caspase-1. The caspase-1 also exists in an inactive precursor in the cytosol and needs proteolytic auto-cleavage, which is catalyzed by the assembly of a multi-protein complex called inflammasome. Inside the circulation, interleukin-18 is bound to its naturally occurring antagonist called interleukin-18 binding protein. The antagonist is induced as a negative feedback to increased interleukin-18 production. It protects body cells and tissues from the potentially destructive and harmful proinflammatory effects of the cytokine. Several researchers have reported that the concentrations and biological activities of the cytokine are increased in the circulation of HIV-infected patients. Unlike interleukin-18, the concentrations of its antagonist, interleukin-18 binding protein, are decreased in these persons. The cytokine may play a major role in the development and pathogenesis of AIDS in HIV-infected persons. Insufficient/lack of interleukin-12 and related cytokines may compromise the ability of interleukin-18 to induce interferon-gamma production from natural killer and T-cells. By inducing production of T-helper 2-type cytokines like interleukin-4, -5, -9, and -13 from basophils and mast cells, interleukin-18 promotes the development and differentiation of CD4+ naive T-cells into T-helper 2-type effector cells, which blunt anti-HIV immunity. The effect may be more pronounced in HIV-infected persons with compromised production of interleukin-12. Interleukin-18 also directly enhances viral replication. Because of its proapoptotic effects, the cytokine decreases survivability and promotes the death of various immune and nonimmune cells. It has also been documented to play a role in the depletion and wasting of subcutaneous fat from the limbs and face. The wasting is a characteristic feature of HIV-associated lipodystrophy. The cytokine is also likely to be involved in the higher incidence of atherosclerotic plaques and systemic insulin resistance in these patients. Finally, increased production of the cytokine in the brain may lead to motor and cognitive dysfunctions, leading to the development of HIV-associated dementia. In conclusion, increased interleukin-18 concentrations in HIV-infected persons are likely to play an important role in the development and progression of the infection toward AIDS and associated clinical conditions. Therefore, its neutralization may represent an appropriate and useful immunotherapeutic strategy in these patients. It may delay AIDS progression and improve the immune status of infected persons. The best way to achieve this goal may be using exogenous interleukin-18 binding protein.
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PMID:Role of interleukin-18 in the development and pathogenesis of AIDS. 1965 53


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