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)

T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1beta-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1beta and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the clinical course and transcription rate of proinflammatory cytokines such as TNF-alpha, IL-1beta, IFN-gamma, and IL-6. A reduction of EAE incidence and severity is observed in caspase-1-deficient mice, depending on the immunogenicity and on the amount of the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incidence correlates with defective development of anti-MOG IFN-gamma-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord homogenate or MOG35-55 peptide, by the caspase-1-inhibitor Z-Val-Ala-dl -Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These results indicate that caspase-1 plays an important role in the early stage of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS.
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PMID:Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. 1045 74

IL-12 and IL-18 are IFN-gamma-inducing cytokines. In the present study, the role of endogenous IL-18 in the induction of IFN-gamma by IL-12 was investigated in mice. In the presence of a specific inhibitor of caspase-1 (also known as IL-1beta-converting enzyme, or ICE) IL-12-induced IFN-gamma from splenocytes was reduced by 85%. Using splenocytes from ICE-deficient mice, IL-12-induced IFN-gamma was reduced by 80%. However, the role of ICE was not through processing and release of IL-1beta. Neutralizing anti-IL-18 IgG reduced IL-12-induced IFN-gamma in splenocytes by 85%. Splenocytes cultured in vitro spontaneously released IL-18 into the extracellular compartment over time. Extracellular levels of IL-18 significantly correlated with IL-12-induced IFN-gamma and were reduced in cells obtained from ICE-deficient mice. In vivo, IL-12 administration increased circulating levels of IL-18 in wild-type mice but not in ICE-deficient mice. Both neutralization of IL-18 and ICE deficiency significantly reduced induction of circulating IFN-gamma in mice receiving IL-12. The IL-18 precursor was constitutively expressed in the livers and spleens of untreated mice. Furthermore, administration of IL-12 significantly increased liver-associated IL-18 levels. These data demonstrate that endogenous, ICE-cleaved IL-18 significantly contributes to induction of IFN-gamma by IL-12.
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PMID:IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. 1049 11

Human normal and malignant T cells cease to proliferate, down-modulate Bcl-2 expression, and undergo apoptosis when cultured in the presence of NO-donor compounds (sodium nitroprusside and NOC12) for 48 h. At 72 h, cells that evade apoptosis start to proliferate again, overexpress both chains of the IFN-gammaR, and thus become susceptible to apoptosis in the presence of IFN-gamma. By contrast, in the presence of IFN-gamma, no apoptosis, but an increase of proliferation was displayed by control cultures of T cells not exposed to NO and not overexpressing IFN-gammaR chains. The NO-induced cell surface overexpression of IFN-gammaR chains did not affect the transduction of IFN-gamma-mediated signals, as shown by the expression of the transcription factor IFN regulatory factor 1 (IRF-1). However, transduction of these signals was quantitatively modified, because IFN-gamma induces enhanced levels of caspase-1 effector death in NO-treated cells. These findings identify NO as one of the environmental factors that critically govern the response of T cells to IFN-gamma. By inducing the overexpression of IFN-gammaR chains, NO decides whether IFN-gamma promotes cell proliferation or the induction of apoptosis.
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PMID:Nitric oxide suppresses human T lymphocyte proliferation through IFN-gamma-dependent and IFN-gamma-independent induction of apoptosis. 1051 Mar 54

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

Histamine (10-7 to 10-4 M) concentration-dependently stimulated the production of IL-18 and IFN-gamma and inhibited the production of IL-2 and IL-10 in human PBMCs. Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of histamine on cytokine production were all antagonized by H2 receptor antagonists ranitidine and famotidine in a concentration-dependent manner, but not by H1 and H3 receptor antagonists. Selective H2 receptor agonists, 4-methylhistamine and dimaprit, mimicked the effects of histamine on five kinds of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 microM, respectively. These findings indicated that histamine caused cytokine responses through the stimulation of H2 receptors. All effects of histamine on cytokine responses were also abolished by the presence of either anti-IL-18 Ab or IL-1beta-converting enzyme/caspase-1 inhibitor, indicating that the histamine action is dependent on mature IL-18 secretion and that IL-18 production is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependently stimulated IL-12 and IFN-gamma production and inhibited the IL-2 and IL-10 production. IFN-gamma production induced by IL-18 was inhibited by anti-IL-12 Ab, showing the marked contrast of the effect of histamine. Thus histamine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18-initiating cytokine cascade without inducing IL-12 production.
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PMID:Histamine is a potent inducer of IL-18 and IFN-gamma in human peripheral blood mononuclear cells. 1084 24

To study the pathophysiological roles of overexpressed caspase-1 (CASP1), originally designated as IL-1 beta-converting enzyme, we generated transgenic mice in which human CASP1 is overexpressed in their keratinocytes. The transgenic mice spontaneously developed recalcitrant dermatitis and skin ulcers, characterized by the presence of massive keratinocyte apoptosis. The skin of the mice contained the active form of human CASP1 and expressed mRNA for caspase-activated DNase, an effector endonuclease responsible for DNA fragmentation. Their skin and sera showed elevated levels of mature IL-18 and IL-1 beta, but not of IFN-gamma. The plasma from these animals induced IFN-gamma production by IL-18-responsive NK cells. Administration of heat-killed Propionibacterium acnes, a potent in vivo type 1 cell inducer, caused IFN-gamma-mediated lethal liver injury in the transgenic mice, which was completely inhibited by treatment with neutralizing anti-IL-18 Ab. These results indicated that in vivo overexpression of CASP1 caused spontaneous apoptotic tissue injury and rendered mice highly susceptible to exogenous type 1 cell-inducing condition in collaboration with endogenously accumulated proinflammatory cytokines.
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PMID:Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. 1087 76

Th1 cells that secrete IFN-gamma are particularly important in protective immunity against intracellular pathogens, including chlamydiae, and IL-18 together with IL-12 are strong inducers of IFN-gamma secretion by CD4 T cells. Because epithelial cells are known to synthesize IL-18, we investigated the effects of Chlamydia trachomatis infection of human epithelial cell lines on IL-18 secretion. We confirmed that several human epithelial cell lines constitutively express pro-IL-18 and that C. trachomatis infection causes cells to secrete mature IL-18. This was observed for several different serovars and biovars of C. trachomatis. Chlamydia-induced secretion of IL-18 from epithelial cells was regulated at the posttranscriptional level and was dependent on the activation of caspase-1. IL-1alpha or other secreted factor(s) from chlamydia-infected epithelial cells as well as chlamydial structural component(s) were not involved in inducing IL-18 secretion. Activation of caspase-1 and increased secretion of mature IL-18 was correlated with chlamydial, but not with host protein synthesis. In contrast to epithelial cell lines, fibroblast cell lines constitutively expressed much lower levels of pro-IL-18 and did not secrete mature IL-18 after chlamydial infection even though caspase-1 was activated. Taken together, the results suggest that a chlamydia-derived factor(s) is essential for the secretion of mature IL-18 through caspase-1 activation in infected epithelial cells.
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PMID:Chlamydia trachomatis infection of epithelial cells induces the activation of caspase-1 and release of mature IL-18. 1090 51

The trisomy of human chromosome 21 (Down syndrome) is the leading genetic cause of learning difficulties in children, and predisposes this population to the early onset of the neurodegeneration of Alzheimer's disease. Down syndrome is associated with increased interferon (IFN) sensitivity resulting in unexpectedly high levels of IFN inducible gene products including Fas, complement factor C3, and neuronal HLA I which could result in a damaging inflammatory reaction in the brain. Consistent with this possibility, we report here that the trisomy 16 mouse fetus has significantly increased whole brain IFN-gamma and Fas receptor immunoreactivity and that cultured whole brain trisomy 16 mouse neurons have increased basal levels of caspase 1 activity and altered homeostasis of intracellular calcium and pH. The trisomic neurons also showed a heightened sensitivity to the increase in both Fas receptor levels and caspase 1 activity we observed when IFN-gamma was added to the neuron culture media. Because of the autoregulatory nature of IFN activity, and the IFN inducing capability of caspase-1-activated cytokine activity, our data argue in favor of the possibility of an interferon-mediated, self-perpetuating, inflammatory response in the trisomy brain that could subserve the loss of neuron viability seen in this trisomy 16 mouse model for Down syndrome.
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PMID:Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis. 1131 23

The interleukins (IL)-1beta and IL-18 represent potent players in the proinflammatory cytokine cascade. Their activation is regulated predominantly through the IL-1-converting enzyme (ICE)/caspase-1. The role of caspases in the secretion of IL-1beta and IL-18, as well as in the release of the secondary-induced cytokines IL-12 and interferon (IFN)-gamma in whole blood from septic patients compared to healthy controls, was studied. Inhibition of caspase activity by Z-VAD significantly reduced lipopolysaccharide (LPS) and Staphylococcus aureus (SAC) induced release of mature IL-1beta in septic patients and controls. In contrast, in whole blood from septic patients significantly elevated basal level of IL-18 were found, which could neither be further increased by LPS or SAC, nor be inhibited by Z-VAD. Release of IL-12 p40 was significantly lower in septic patients compared to controls and was not affected by Z-VAD. Despite high levels of IL-18, IFN-gamma was not detected in whole blood from septic patients even after stimulation with SAC or LPS. Thus, during sepsis, caspases participate in the processing of IL-1beta, whereas maturation of IL-18 during sepsis appears to be independent of caspases. The lack of IFN-gamma release seen in septic patients could be attributed to low IL-12 release rather than to diminished IL-18 release.
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PMID:Differential effect of caspase inhibition on proinflammatory cytokine release in septic patients. 1102 39

Caspase-1, the IL-1beta converting enzyme (ICE), is required for intracellular processing/maturation of IL-1beta and IL-18. NO releasing nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID derivatives that spare the gastric mucosa. Here, we tested the hypothesis that NCX-4016, a NO-aspirin derivative, inhibits proinflammatory cytokine release from endotoxin (LPS)-challenged monocytes. Our results demonstrated that exposing LPS-stimulated human monocytes to NCX-4016 resulted in a 40-80% inhibition of IL-1beta, IL-8, IL-12, IL-18, IFN-gamma, and TNF-alpha release with an EC(50) of 10-20 microM for IL-1beta and IL-18. Incubating LPS-primed monocytes with NCX-4016 resulted in intracellular NO formation as assessed by measuring nitrite/nitrate, intracellular cGMP concentration, and intracellular NO formation. Exposing LPS-stimulated monocytes to aspirin or celecoxib caused a 90% inhibition of prostaglandin E(2) generation but had no effect on cytokine release. NCX-4016, similar to the NO donor S-nitroso-N-acetyl-D-L-penicillamine, inhibited caspase-1 activity with an EC(50) of approximately 20 microM. The inhibition of caspase-1 by NCX-4016 was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented ICE activation as measured by assessing the release of ICE p20 subunit. IL-18 immunoneutralization resulted in a 60-80% reduction of IL-1beta, IL-8, IFN-gamma, and TNF-alpha release from LPS-stimulated monocytes. Taken together, these data indicate that incubating human monocytes with NCX-4016 causes intracellular NO formation and suppresses IL-1beta and IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition is a new, cycloxygenase-independent antiinflammatory mechanism of NO-aspirin.
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PMID:IL-1 beta converting enzyme is a target for nitric oxide-releasing aspirin: new insights in the antiinflammatory mechanism of nitric oxide-releasing nonsteroidal antiinflammatory drugs. 1104 58


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