Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies indicate that polymicrobial sepsis can markedly increase inducible macrophage Ao (nonnecrotic cellular suicide) and that this is associated with decreased M phi function. In vitro studies suggest that M phi Ao can be induced by IL-1 beta via interleukin-1 beta-converting enzyme (ICE, a cysteine protease), prostanoids, or reactive oxygen/nitrogen. However, the mechanism(s) underlying this process in septic M phi remains unknown. To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-operation. Twenty-four hours thereafter, M phi were isolated from the peritoneum (PM phi) and liver (LM phi). Macrophage monolayers were treated with LPS (10 micrograms/ml) alone (Cont) or in the presence of iodoacetamide (Iodo, 5 mM), N-methylmalamide (meth, 5 mM), ibuprophen (Ibu, 40 micrograms/ml), N-methyl-L-arginine (LNMA, 0.4 mM), or superoxide dismutase (SOD, 60,000 U/ml) for 24 hr. The extent of Ao was determined using an enzyme-linked immunosorbent cell-death assay, which detects the presence of cytoplasmic oligonucleosomes measured as optical density. The results indicate that both PM phi and LM phi from septic animals exhibit increased Ao over cells from sham animals. However, only the nonspecific cysteine protease inhibitors (Iodo and meth) and the NO inhibitor LNMA blocked septic mouse M phi Ao. Furthermore, only PM phi from CLP mice treated with Iodo, but not LNMA or IBU, showed an improved capacity to release IL-6. We conclude that increased M phi Ao seen during sepsis appears to be mediated by both ICE-like cysteine protease activation and NO release but the level/mechanism of action of these inhibitors differs.
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PMID:Inducible macrophage apoptosis following sepsis is mediated by cysteine protease activation and nitric oxide release. 924 58

IL-1 alpha and IL-1 beta bind to receptors termed the type I and type II IL-1 receptors. The type I IL-1 receptor is responsible for specific signaling, while the type II IL-1 receptor functions as a nonsignaling decoy receptor. To determine the effect of a defect in IL-1-mediated signaling, mice have been produced with a genetically disrupted type I IL-1 receptor gene. Mice lacking type I IL-1 receptors are of normal vigor and exhibit no overt phenotype. B cells from type I IL-1R-/- mice activated in vitro with anti-IgM do not proliferate in response to IL-1, but do so in response to IL-4. Injection of murine IL-1 alpha does not induce detectable serum IL-6 levels in type I IL-1R-/- mice, but equivalent levels are produced in response to LPS. Type I IL-1R-/- mice have normal serum Ig levels and generate equivalent primary and secondary Ab responses as wild-type mice. In response to LPS, acute phase protein mRNA induction are equivalent in type I IL-1R-/- and wild-type mice. Type I IL-1R-/- mice do not differ from control mice in susceptibility to either a lethal challenge with D-galactosamine plus LPS or high dose LPS. Interestingly, ICE-/-/type I IL-1R-/- double mutant mice are resistant to high dose LPS. Type I IL-1R-/- mice backcrossed to the C57BL/6 background were as equally resistant as wild-type mice to Listeria monocytogenes.
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PMID:Phenotypic and functional characterization of mice that lack the type I receptor for IL-1. 931 35

Interleukin-1 beta (IL-1 beta) is a pleiotropic proinflammatory cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature precursor protein into an active secretory form by the intracellular protease caspase-1 (formerly termed IL-1-converting enzyme [ICE]). Caspase-1 belongs to a rapidly growing family of cysteine proteases with substrate specificity for aspartate involved in cellular apoptosis. We have used an assay determining the caspase-1 activity based on cleavage of a fluorogenic peptide substrate to elucidate its role in lipopolysaccharide (LPS)-induced secretion of IL-1 beta. We show that LPS induces moderate caspase-1 activity in the monocytic cell line THP-1, in freshly isolated peripheral blood monocytes, and in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent fashion. Caspase-1 activation by LPS was associated with cleavage of the IL-1 beta precursor protein that was followed by release of the mature IL-1 beta protein in monocytic cells. In contrast, subsequent release of IL-1 beta by HUVECs was not significant. LPS-induced caspase-1 activation appeared not to result from modulation of caspase-1 transcript accumulation and inhibition of caspase-1 activity was accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable of alleviating the release of mature IL-1 beta. Taken together, these results show that LPS moderately activates caspase-1 and that caspase-1 activation contributes to LPS induction of IL-1 beta secretion.
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PMID:Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. 942 12

IL-1 beta-converting enzyme (ICE), also known as caspase-1, subserves two dichotomous biologic roles. It processes newly synthesized pro-IL-1 beta to yield the active cytokine and, as the human homologue of the Caenorhabditis elegans gene product, ced-3, it also induces cellular apoptosis through the cleavage of key intracellular structural and regulatory proteins and through the catalytic activation of other caspase family members. We show here that two different proinflammatory stimuli, LPS and granulocyte-macrophage-CSF, up-regulate the expression of both ICE and IL-1 beta in human polymorphonuclear neutrophils, and that the ICE-dependent cleavage of pro-IL-1 beta results in delayed expression of the constitutive cell death program. The apoptotic delay can be blocked by inhibiting tyrosine kinases or NF-kappa B activation and by inhibiting protein synthesis. Since an antisense oligonucleotide for IL-1 beta, a blocking Ab to IL-1 beta, and preincubation with the IL-1R antagonist all prevent the delay in apoptosis, we conclude that IL-1 beta acts in an autocrine manner to inhibit granulocyte programmed cell death. We conclude that caspase-1 (ICE) subserves both pro- and antiapoptotic roles; the latter role is evident during inflammation as an inhibition of spontaneous neutrophil apoptosis through the processing of IL-1 beta. The ICE-dependent activation of IL-1 beta may represent a common autocrine pathway for the divergent stimuli that inhibit the constitutive expression of neutrophil programmed cell death during inflammation.
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PMID:The IL-1 beta-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1 beta. 967 Sep 75

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

Members of the tumor necrosis factor receptor (TNFR) superfamily have an important role in the induction of cellular signals resulting in cell growth, differentiation and death. TNFR-1 recruits and assembles a signaling complex containing a number of death domain (DD)-containing proteins, including the adaptor protein TRADD and the serine/threonine kinase RIP, which mediates TNF-induced NF-kappa B activation. RIP also recruits caspase-2 to the TNFR-1 signaling complex via the adaptor protein RAIDD, which contains a DD and a caspase-recruiting domain (CARD). Here, we have identified a RIP-like kinase, termed CARDIAK (for CARD-containing interleukin (IL)-1 beta converting enzyme (ICE) associated kinase), which contains a serine/threonine kinase domain and a carboxy-terminal CARD. Overexpression of CARDIAK induced the activation of both NF-kappa B and Jun N-terminal kinase (JNK). CARDIAK interacted with the TNFR-associated factors TRAF-1 and TRAF-2, and a dominant-negative form of TRAF-2 inhibited CARDIAK-induced NF-kappa B activation. Interestingly, CARDIAK specifically interacted with the CARD of caspase-1 (previously known as ICE), and this interaction correlated with the processing of pro-caspase-1 and the formation of the active p20 subunit of caspase-1. Together, these data suggest that CARDIAK may be involved in NF-kappa B/JNK signaling and in the generation of the proinflammatory cytokine IL-1 beta through activation of caspase-1.
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PMID:Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. 970 38

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50

Involvement of proteases has been postulated in several neurodegenerative processes. Accordingly, protease inhibition has been proposed as a potential therapeutic tool to limit damage in some neuropathological states. The timed turn-over of proteins is, however, an essential biochemical process and its prolonged block may be dangerous to the cell. We report here data on toxicity consequent to 24-h exposure of cerebellar granule neurons in culture to inhibitors of different classes of proteases. Inhibition of calpains (calcium-activated cysteine proteases) resulted in dose-dependent neuronal death which largely occurred through apoptotic process. Leupeptin, an inhibitor acting on a broad spectrum of cellular serine proteases, was less toxic but resulted in definite morphological alteration of the cells. On the contrary, inhibitors of caspases, proteases belonging to the ICE (interleukin 1-beta converting enzyme) family, did not apparently damage granule neurons upon exposure for 24 h to high concentrations (up to 200 microM) of two inhibitors specific for ICE (Ac-YAVD-CHO) and CPP-32 (Ac-DEVD-CHO), respectively. These results suggest that inhibition of proteases that are activated by stressful stimuli but are not essential for the normal functioning of healthy cells, as it is likely the case for caspases, may not be harmful to neurons. Instead, the potential risks and side effects of prolonged inhibition of proteases such as calpains, that regulate the disposal and the turn-over of key cellular proteins, should be carefully tested in the assessment of possible neuroprotective roles.
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PMID:Differential toxicity of protease inhibitors in cultures of cerebellar granule neurons. 978 92

When injected intravenously into humans and animals, interleukin-1 beta (IL-1 beta) is perhaps the most potent of the endogenous pyrogens. However, IL-1 beta is initially synthesized as a relatively inactive precursor molecule (proIL-1 beta) which lacks a signal peptide and hence remains inside the cell. To be active as a fever-producing molecule, proIL-1 beta must first be processed to an active mature molecule and secreted. Although several enzymes associated with inflammatory tissues are capable of processing proIL-1 beta into an active molecule in the extracellular compartment, the IL-1 beta converting enzyme (ICE, also called caspase-1) cuts intracellular proIL-1 beta after the aspartic acid residue in position 116, resulting in a highly active mature IL-1 beta that is secreted into the extracellular space. IL-18 is also initially synthesized as an inactive precursor molecule (proIL-18) lacking a signal peptide. IL-18 is a member of the IL-1 family, and like IL-1 beta, proIL-18 is cleaved by ICE to yield an active molecule. However, unlike IL-1 beta, IL-18 is not an endogenous pyrogen following intraperitoneal injection into mice. Nevertheless, IL-18 may contribute to inflammation and fever because IL-18 is a potent inducer of tumor necrosis factor, chemokines, and interferon-gamma production.
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PMID:Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. 991 59

The processing and release of 31-kDa proIL-1 beta to the mature 17-kDa form of IL-1 beta are still poorly understood. To help elucidate the mechanisms involved in IL-1 beta processing and release, we measured IL-1 beta forms released from endotoxin-stimulated monocytes by immunoprecipitation of [35S]methionine-labeled protein, by Western blots, and by our recently developed ELISA specific for proIL-1 beta. Our studies demonstrate that in addition to the 17-kDa mature IL-1 beta, IL-1 beta is also released as 31-, 28-, and 3-kDa molecules. The 31-kDa-released form of proIL-1 beta represented 20-40% of the total released IL-1 beta, as measured by SDS-PAGE with densitometry. This released proIL-1 beta was susceptible to ICE processing; however, this proIL-1 beta was not detectable by either a mature or proIL-1 beta-specific ELISA, suggesting that release induces a conformational change. The ELISA inability to detect proIL-1 beta was not due to inadequate sensitivity or subsequent degradation in the ELISA. Furthermore, while immunoaffinity-purified cytosolic proIL-1 beta could complex the type II IL-1R, released proIL-1 beta did not. Finally, the absence of a band shift in nondenaturing gel electrophoresis excluded proIL-1 beta binding to another protein. These findings imply that IL-1 beta is exported from monocytes as 3-, 17-, 28-, and 31-kDa forms and that the released 31-kDa form differs from cytosolic proIL-1 beta.
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PMID:Endotoxin-stimulated monocytes release multiple forms of IL-1 beta, including a proIL-1 beta form whose detection is affected by export. 1020 30


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