Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin-1 beta converting enzyme (ICE) is the cysteine proteinase responsible for cleaving the 31-kDa interleukin-1 beta (IL-1 beta) precursor to its active 17-kDa form. In lipopolysaccharide-stimulated cultured macrophages, induction of apoptosis but not necrosis effectively induces conversion of the IL-1 beta precursor to its mature form and results in the concomitant release of the mature cytokine from the cell. To determine whether ICE activity is required for macrophage apoptosis, we have exposed macrophages either to 5 mM ATP or to alloreactive cytolytic T lymphocytes (CTL) in the absence and presence of the ICE inhibitor peptide YVAD-chloromethylketone (YVAD-emk). Activated cells treated with YVAD-emk and ATP or CTL showed no mature IL-1 beta in either the cell lysates or the culture supernatants, indicating effective inhibition of ICE activity; however, the YVAD-treated macrophages showed no detectable change in 51Cr release or nuclear fragmentation, indicating failure to inhibit apoptotic cell death. Thus, in these cells, YVAD-emk uncouples IL-1 beta processing and apoptosis.
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PMID:Macrophage apoptosis in the absence of active interleukin-1 beta-converting enzyme. 749 71

1. The aim of this study was to determine whether a synthetic inhibitor of the interleukin-1 beta converting enzyme (ICE) displays oral activity in models of inflammation. 2. To this end, the ICE inhibitor, SDZ 224-015, was examined in rat paw oedema, pyrexia and nociception tests. 3. SDZ 224-015 (0.3-300 micrograms kg-1) potently reduced carrageenin-induced paw oedema, with an oral ED50 of approximately 25 micrograms kg-1. This effect was independent of endogenous glucocorticoid, as shown by retention of activity upon adrenalectomy. 4. Pyrexia induced by lipopolysaccharide (0.1 mg kg-1 s.c.) or by interleukin-1 beta (100 ng i.v.) was also reduced, over a similar dose-range to oedema (oral ED50s 11 micrograms kg-1 and 4 micrograms kg-1 respectively). 5. SDZ 224-015 (0.2-5 mg kg-1, p.o.) displayed analgesic activity in the Randall-Selitto yeast-inflamed paw pressure test, significant at a dose of 1 mg kg-1, p.o. 6. Thus, SDZ 224-015 has potent oral activity in several acute models for inflammation, suggesting that ICE inhibitors may constitute a novel type of anti-inflammatory agent.
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PMID:Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224-015, an inhibitor of the interleukin-1 beta converting enzyme. 758 78

IL-1 beta-converting enzyme (ICE) cleaves pro-IL-1 beta to generate mature IL-1 beta. ICE is homologous to other proteins that have been implicated in apoptosis, including CED-3 and Nedd-2/lch-1. We generated ICE-deficient mice and observed that they are overtly normal but have a major defect in the production of mature IL-1 beta after stimulation with lipopolysaccharide. IL-1 alpha production is also impaired. ICE-deficient mice are resistant to endotoxic shock. Thymocytes and macrophages from the ICE-deficient animals undergo apoptosis normally. ICE therefore plays a dominant role in the generation of mature IL-1 beta, a previously unsuspected role in production of IL-1 alpha, but has no autonomous function in apoptosis.
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PMID:Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. 785 82

Interleukin-1 (IL-1) plays a crucial role in the development of the pathophysiological responses to infection and inflammation. However, the relative contributions of IL-1 alpha and IL-1 beta remain to be clarified. IL-1 beta-deficient mice are a powerful tool to investigate the specific role of IL-1 beta in various experimental conditions. In this report, we summarize the response of IL-1 beta deficient mice to two different inflammatory stimuli, turpentine and endotoxin. Although IL-1 beta-deficient mice respond normally to the systemic administration of lipopolysaccharide (LPS), they do not develop an acute-phase response in the localized tissue damage model of turpentine injection. The results obtained using the IL-1 beta-deficient mice are compared here with those observed in the IL-1 beta-converting enzyme-deficient, IL-6-deficient, tumour necrosis factor-receptor p55-deficient, and interferon-gamma-receptor-deficient mice.
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PMID:The inflammatory response in interleukin-1 beta-deficient mice: comparison with other cytokine-related knock-out mice. 861 94

Pro interleukin-1 beta converting enzyme (ICE) activity in the pituitary was found to be significantly increased 4 h after intraperitoneal injection of E. coli lipopolysaccharides, when distribution and inducibility of the enzyme was studied in the adult rat brain and the adrenal gland, using an artificial fluorescence peptide substrate. The same lipopolysaccharide treatment induced ICE mRNA levels in the pituitary, adrenal gland and hypothalamus as studied by reverse transcript-polymerase chain reaction.
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PMID:Regionally specific induction of ICE mRNA and enzyme activity in the rat brain and adrenal gland by LPS. 870 99

The proinflammatory cytokines which are released by activated accessory immune cells during the course of an infection have profound effects on the brain. These effects include activation of the hypothalamic-pituitary-adrenal axis, fever and behavioral depression. They are mediated by cytokines which are synthesized and released in the brain, in response to peripherally released cytokines. Glucocorticoids have potent regulatory effects on the synthesis of cytokines by activated macrophages and monocytes. These hormones are also able to regulate the synthesis and action of cytokines in the brain, as demonstrated by the sensitizing effects of adrenalectomy and the depressing effects of stress on the increased cytokine and interleukin-1 beta converting enzyme gene expression that occurs in response to lipopolysaccharide in mice. Preliminary experiments indicate that another way glucocorticoids can contribute to down regulation of the IL-1 system is by increasing the expression of the type II IL-1 receptor in the brain. The regulatory effects of glucocorticoids on cytokine expression in the brain have functional consequences, as demonstrated by the enhanced sensitivity of adrenalectomized animals to the behavioral actions of centrally administered LPS and IL-1. The effects of adrenalectomy are inhibited by compensation with a corticosterone implant and they are mimicked by administration of the type II glucocorticoid receptor, RU 38486. The regulatory role of glucocorticoids on the expression and action of cytokines in the brain makes these hormones and their mechanisms of action key targets for therapeutic interventions in psychopathology and neuropathology.
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PMID:Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences. 926 51

Shigella, the etiological agent of bacillary dysentery, rapidly kills human monocyte-derived macrophages in vitro. Wild-type Shigella flexneri, but not a nonvirulent derivative, induced human macrophage apoptosis as determined by morphology and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). Shigella-mediated macrophage cell death was blocked by the peptide inhibitors of caspases, acetyl-Tyr-Val-Ala-Asp-aldehyde (acetyl-YVAD-CHO) and acetyl-Tyr-Val-Ala-Asp-chloromethylketone (acetyl-YVAD-CMK). Protection from apoptosis by YVAD was observed in monocytes matured in the presence or absence of colony-stimulating factors (CSF) like macrophage-CSF or granulocyte-macrophage-CSF. Furthermore, lipopolysaccharide (LPS) or gamma interferon (IFN-gamma) rendered human macrophages partially resistant to Shigella cytotoxicity. Macrophages stimulated with either LPS or IFN-gamma were also protected by YVAD from Shigella-induced cell death. During Shigella infections of human macrophages, interleukin-1beta (IL-1beta) was cleaved to the mature form. IL-1beta maturation was severely retarded by YVAD, indicating that IL-1beta-converting enzyme (ICE; caspase 1) is activated in Shigella-induced apoptosis. The finding that Shigella induces apoptosis in human macrophages by activating ICE supports the hypothesis that the acute inflammation characteristic of shigellosis is initially triggered by apoptotic macrophages which release mature IL-1beta during programmed cell death.
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PMID:The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages. 939 11

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

Immune system activation induces increase in expression level and enzymatic activity of interleukin-1 beta converting enzyme (ICE) in rat brain. As ICE has been implicated in apoptotic cell death, a possible link may exist between immune system activation by bacterial endotoxic lipopolysaccharide (LPS) and apoptosis in rat brain. The aim of this study was to investigate possible effect of acute (5.5 h) or chronic (5 days) intraperitoneal (i.p.) administration and central injection of LPS on brain apoptotic cell death. Body temperature was continuously monitored for fever, a hallmark of immune activation. Detection of apoptotic cell death was carried out by using in situ labelling of DNA fragmentation in various brain structures. Despite the chronic or the acute pyrogenic effects of LPS, no evidence for apoptotic cell death was observed in any of the brain areas analysed, including hippocampus, hypothalamus, area postrema, subfornical organ, organum vasculosum of the lamina terminalis and nucleus tractus solitaris. Other well-known sites of apoptotic cell death, including brain of ischemic rat, mammary gland of post-lactating rat and rat intestine as well as Dnase-treated rat brain slices, were used as positive controls. These results suggest that ICE activation during fever development is dissociated from cell death by apoptosis in rat brain. Unlike peripheral targets of immunocompetent cytokines, a protective system, yet to be defined, may be present in the central nervous system and block the deleterious effects of infectious agents and cytokines.
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PMID:Lipopolysaccharide-induced fever is dissociated from apoptotic cell death in the rat brain. 973 32

A series of novel 6-substituted 5,6-dihydro-5-hydroxy-alpha-pyrone esters, 1 approximately 3, isolated from fermentations of a Phomopsis sp. (Xenova culture collection no. X22502) have been identified as inhibitors of lipopolysaccharide (LPS)-induced cytokine production. These include the (6S)-4,6-dimethyldodecadien-2E,4E-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2E-enoic acid moiety at the 6-position of the alpha-pyrone ring. (6S)-4,6-Dimethyl-2E,4E-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited LPS-induced tumour necrosis factor alpha (TNFalpha) production by U937 cells and LPS-induced interleukin 1beta (IL-1beta) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selective for IL-1beta relative to TNFalpha. The inhibition of IL-1beta production by 1 involved a post-translational mechanism of action at the level of IL-1beta secretion as demonstrated by the lack of an effect on cell-associated IL-1beta production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.
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PMID:A novel (6S)-4,6-dimethyldodeca-2E,4E-dienoyl ester of phomalactone and related alpha-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity. 1060 55


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