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)

Interferon-gamma-inducing factor (IGIF, interleukin-18) is a recently described cytokine that shares structural features with the interleukin-1 (IL-1) family of proteins and functional properties with IL-12. Like IL-12, IGIF is a potent inducer of interferon (IFN)-gamma from T cells and natural killer cells. IGIF is synthesized as a biologically inactive precursor molecule (proIGIF). The cellular production of IL-1beta, a cytokine implicated in a variety of inflammatory diseases, requires cleavage of its precursor (proIL-1beta) at an Asp-X site by interleukin-1beta-converting enzyme (ICE, recently termed caspase-1). The Asp-X sequence at the putative processing site in proIGIF suggests that a protease such as caspase-1 might be involved in the maturation of IGIF. Here we demonstrate that caspase-1 processes proIGIF and proIL-1beta with equivalent efficiencies in vitro. A selective caspase-1 inhibitor blocks both lipopolysaccharide-induced IL-1beta and IFN-gamma production from human mononuclear cells. Furthermore, caspase-1-deficient mice are defective in lipopolysaccharide-induced IFN-gamma production. Our results thus implicate caspase-1 in the physiological production of IGIF and demonstrate that it plays a critical role in the regulation of multiple proinflammatory cytokines. Specific caspase-1 inhibitors would provide a new class of anti-inflammatory drugs with multipotent action.
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PMID:Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. 912 87

Recently, human interleukin 18 (hIL-18) cDNA was cloned, and the recombinant protein with a tentatively assigned NH2-terminal amino acid sequence was generated. However, natural hIL-18 has not yet been isolated, and its cellular processing is therefore still unclear. To clarify this, we purified natural hIL-18 from the cytosolic extract of monocytic THP.1 cells. Natural hIL-18 exhibited a molecular mass of 18.2 kDa, and the NH2-terminal amino acid was Tyr37. Biological activities of the purified protein were identical to those of recombinant hIL-18 with respect to the enhancement of natural killer cell cytotoxicity and interferon-gamma production by human peripheral blood mononuclear cells. We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. These results suggest that the production and processing of natural hIL-18 are regulated by two processing enzymes, caspase-1 and caspase-3, in THP.1 cells.
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PMID:Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells. 933 40

The interleukin-1 (IL-1) family comprises IL-1 alpha and IL-1 beta and an endogenous IL-1 receptor antagonist (IL-1ra). IL-1 has diverse actions in the brain and has been implicated in both acute and chronic neurodegeneration. However, neither IL-1 alpha nor IL-1 beta are neurotoxic per se in vivo, so other IL-1 related ligands may be important in neurodegeneration. The cytokine interleukin-18 (also called interferon gamma inducing factor, IGIF) was first isolated from the liver of mice during toxic shock. It was later proposed as a member of the IL-1 family, based on protein sequence homology with IL-1 beta and IL-1ra, and has tentatively been called IL-1 gamma. We cloned IL-18 from adult rat brain and demonstrated, by RT-PCR, that it is expressed constitutively in cerebellum, hippocampus, hypothalamus, cortex and striatum. Rat brain IL-18 shows close homology to mouse and human IL-18, and to the recently published sequence from the rat adrenal gland. Mouse pro-IL-18 and pro-IL-1 beta are processed by caspase-1. We demonstrate that caspase-1 also cleaves rat IL-18 in vitro and that the caspase inhibitor, zVAD-DCB inhibits this cleavage.
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PMID:Cloning of rat brain interleukin-18 cDNA. 970 48

Procytokine processing by caspase-1 is required for the maturation and release of IL-1beta and IFN-gamma-inducing factor (IGIF) (or IL-18) from activated macrophages (Mphi). Nitric oxide (NO) has emerged as a potent inhibitor of cysteine proteases. Here, we tested the hypothesis that NO regulates cytokine release by inhibiting IL-1beta-converting enzyme (ICE) or caspase-1 activity. Activated RAW264.7 cells released four to five times more IL-1beta, but not TNF-alpha, in the presence of the NO synthase inhibitor N(G)-monomethyl-L-arginine. Stimulated peritoneal Mphi from wild-type mice (inducible NO synthase (iNOS)+/+) also released more IL-1beta if exposed to N(G)-monomethyl-L-arginine, whereas Mphi from iNOS knockout mice (iNOS-/-) did not. Inhibition of NO synthesis in stimulated RAW264.7 cells also resulted in a threefold increase in intracellular caspase-1 activity. The NO donor S-nitroso-N-acetyl-DL-penicillamine inhibited caspase-1 activity in cells as well as the activity of purified recombinant caspase-1 and also prevented the cleavage of pro-IL-1beta and pro-IGIF by recombinant caspase-1. The inhibition of caspase-1 by NO was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. An in vivo role for the regulation of caspase-1 by NO was established in iNOS knockout animals, which exhibited significantly higher plasma levels of IL-1beta and IFN-gamma than their wild-type counterparts at 10 h following LPS injection. Taken together, these data indicate that NO suppresses IL-1beta and IGIF processing by inhibiting caspase-1 activity, providing evidence for a unique role for induced NO in regulating IL-1beta and IGIF release.
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PMID:Nitric oxide prevents IL-1beta and IFN-gamma-inducing factor (IL-18) release from macrophages by inhibiting caspase-1 (IL-1beta-converting enzyme). 978 Jan 84

Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.
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PMID:IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. 989 78

The list of interleukins is growing at a steady rate. Although, it is over 8 years since the initial description of interferon gamma inducing factor (IGIF, now called IL-18), this novel cytokine is still not well characterised. However, the data were sufficient to support the testing of IL-18 in experimental tumour therapy. IL-18 is produced mainly by macrophages. Similarly to IL-1beta, IL-18 does not possess a signal sequence allowing direct secretion through the plasma membrane. Although, the exact mechanism of IL-18 secretion is not confirmed, it seems that, like IL-1beta, IGIF is processed by the cysteine proteases belonging to caspase family, especially by ICE (interleukin 1beta converting enzyme). Among the target cells responding to IL-18 are T lymphocytes and NK cells, which, under the influence of IL-18, produce substantial amounts of IFN-gamma. In this respect IL-18 seems to be even stronger than IL-12. Similarly to IL-12, IL-18 stimulates cytotoxicity of T and NK cells. Moreover, it enhances FasL-mediated cytotoxicity of CD4+ T and NK cells. A potential role of IL-18 in tumour immunotherapy is discussed in this article with special emphasis on the similarities with IL-12 and the potential mechanisms of its antitumour activity in preclinical models in mice.
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PMID:Interleukin 18--interferon gamma inducing factor--a novel player in tumour immunotherapy? 1080 13

Acute graft-versus-host disease (aGVHD), the fatal side effects of bone marrow transplantation, was shown to be accompanied by elevation of serum levels of interleukin 18 (IL-18). In this study, the mechanism underlying the accumulation of IL-18 in aGVHD in mice was investigated. Lethally irradiated recipients having transplantation with H-2 disparate donor splenocytes demonstrated aGVHD and contained markedly elevated serum levels of IL-18. In contrast, recipients having transplantation with gld/gld spleen cells, which lack functional Fas ligand (FasL), contained only normal ranges of IL-18, indicating FasL-mediated IL-18 release in aGVHD. The wild-type hosts engrafted with caspase-1-deficient cells revealed marked increases of IL-18 similar to those engrafted with wild-type cells, whereas caspase-1-deficient recipients engrafted with wild-type cells showed only a slight elevation of serum IL-18, indicating that IL-18 elevation is derived from host cells in a caspase-1-dependent manner. These results suggest FasL-mediated caspase-1-dependent IL-18 secretion in aGVHD in mice.
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PMID:Fas ligand-induced caspase-1-dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease. 1141 86

ATP stimulation of cell surface P2X7 receptors results in cytolysis and cell death of macrophages. Activation of this receptor in bacterial lipopolysaccharide (LPS)-activated macrophages or monocytes also stimulates processing and release of the cytokine interleukin-1beta(IL-1beta) through activation of caspase-1. The cytokine interleukin 18 (IL-18) is also cleaved by caspase-1 and shares pro-inflammatory characteristics with IL-1beta. The objective of the present study was to test the hypothesis that IL-1beta, IL-18, and/or caspase-1 activation contribute directly to macrophage cell death induced by LPS and ATP. Macrophages were cultured from normal mice or those in which genes for the P2X7 receptor, IL-1beta, IL-1alpha, IL-18, or caspase-1 had been deleted. Our data confirm the importance of the P2X7 receptor in ATP-stimulated cell death and IL-1beta release from LPS-primed macrophages. We demonstrate that prolonged stimulation with ATP leads to cell death, which is partly dependent on LPS priming and caspase-1, but independent of cytokine processing and release. We also provide evidence that LPS priming of macrophages makes them highly susceptible to the toxic effects of brief exposure to ATP, which leads to rapid cell death by a mechanism that is dependent on caspase-1 but, again, independent of cytokine processing and release.
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PMID:Priming of macrophages with lipopolysaccharide potentiates P2X7-mediated cell death via a caspase-1-dependent mechanism, independently of cytokine production. 1170 16

Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
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PMID:Interleukin-18 and host defense against infection. 1279 54

Recent publications have demonstrated that the protease caspase-1 is responsible for the processing of pro-interleukin 18 (IL-18) into the active form. Studies on cell lines and murine macrophages have shown that the bacterial invasion factor SipB activates caspase-1, triggering cell death. Thus, we investigated the role of SipB in the activation and release of IL-18 in human alveolar macrophages (AM), which are the first line of defense against inhaled pathogens. Under steady-state conditions, AM are a more important source of IL-18 than are dendritic cells (DC) and monocytes. Cytokine production by AM and DC was compared after both types of cells had been infected with a virulent strain of Salmonella enterica serovar Typhimurium and an isogenic sipB mutant, which were used as an infection model. Infection with virulent Salmonella led to marked cell death with features of apoptosis while both intracellular activation and release of IL-18 were demonstrated. In contrast, the sipB mutant did not induce such cell death or the release of active IL-18. The specific caspase-1 inhibitor Ac-YVAD-CMK blocked the early IL-18 release in AM infected with the virulent strain. However, the type of Salmonella infection did not differentially regulate IL-18 gene expression. We concluded that the bacterial virulence factor SipB plays an essential posttranslational role in the intracellular activation of IL-18 and the release of the cytokine in human AM.
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PMID:Human alveolar macrophages infected by virulent bacteria expressing SipB are a major source of active interleukin-18. 1287 16


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