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)

Interleukin (IL)-1 beta-converting enzyme (ICE) cleaves the biologically inactive precursor form of IL-1 beta into mature, bioactive IL-1 beta. Because of the potent effects of IL-1 in blood vessels, we conducted an in situ hybridization study to determine whether ICE mRNA is constitutively expressed in adult rat brain vasculature. Using in situ hybridization histochemistry, we were able to demonstrate that mRNA in blood vessels scattered throughout the brain. In a second set experiments, we found that the genes encoding not only ICE, but also IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), and the IL-1 type I receptor are expressed in brain vasculature. To our knowledge this is the first report documenting the expression of the genes encoding all of the functional elements of the IL-1 system in the same tissue. Our findings have three pathophysiological implications. First, they indicate a possible site where peripheral IL-1 may act in the brain. The vascular IL-1 system stimulates the production of nitric oxide and prostanoids, which could act as mediators of the effects of peripheral IL-1 in the central nervous system. Additionally, vascular IL-1 is known to activate adhesion molecules; our data that the genes encoding the IL-1 system are expressed in brain vasculature further support the concept that IL-1 is implicated in the pathophysiology of atherosclerosis and stroke. Finally, in the context of previous studies documenting that IL-1ra inhibits the effects of IL-1 on endothelial cells, our findings of endogenous IL-1ra mRNA in brain vasculature indicate that IL-1ra might be an endogenous vascular protective agent.
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PMID:Localization of interleukin-1 beta converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Pathophysiological implications. 864 63

In order to investigate the mechanisms how modified lipoproteins enhance foam cell formation, we cultured peripheral blood monocytes with various stimulants and examined the effects of aggregated low-density lipoprotein (agLDL) on cell viability and lipid metabolism. AgLDL could completely inhibit phorbol ester-induced apoptosis, which was accompanied by intracellular cholesterol accumulation. Suppression of apoptosis-promoting proteases, ICE and CPP32, was observed in agLDL-treated cells. This indicates that agLDL accelerates foam cell formation through inhibition of apoptosis and enhancement of lipid accumulation in activated monocytes. By contrast, apoptosis was enhanced when monocytes were cultured with agLDL and M-CSF. Intracellular cholesterol accumulation was not significant in M-CSF treated cells. This suggests that M-CSF may act anti-atherogenic through apoptotic elimination of lipid-baring macrophages and enhanced lipid turnover. Our observation supports the novel hypothesis that regulation of apoptosis may play an important role in the development of atherosclerosis.
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PMID:Regulatory effects of aggregated LDL on apoptosis during foam cell formation of human peripheral blood monocytes. 920 41

Macrophages differentiated from circulating peripheral blood monocytes are essential for host immune responses and have been implicated in the pathogenesis of rheumatoid arthritis and atherosclerosis. In contrast to monocytes, macrophages are resistant to Fas-induced cell death by an unknown mechanism. FLICE (Fas-associated death domain-like interleukin 1beta-converting enzyme)-inhibitory protein (Flip), a naturally occurring caspase-inhibitory protein that lacks the critical cysteine domain necessary for catalytic activity, is a negative regulator of Fas-induced apoptosis. Here, we show that monocyte differentiation into macrophages was associated with upregulation of Flip and a decrease in Fas-mediated apoptosis. Overexpression of Flip protected monocytes from Fas-mediated apoptosis, whereas acute Flip inhibition in macrophages induced apoptosis. Addition of an antagonistic Fas ligand antibody to Flip antisense-treated macrophages rescued cultures from apoptosis, demonstrating that endogenous Flip blocked Fas-induced cell death. Thus, the expression of Flip in macrophages conferred resistance to Fas-mediated apoptosis, which may contribute to the development of inflammatory disease.
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PMID:FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis. 1058 58

T cells are prominent components of both early and late atherosclerotic lesions and the role of Th1/Th2 cells subsets in the evolution and rupture of the plaque is currently under investigation. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exert actions beyond that of simply lowering cholesterol levels, and some effects on immune function have been reported. We studied in vitro the effects of fluvastatin on Th1/Th2 cytokine release in relation to caspase-1 activation, in human peripheral-blood mononuclear cells (PBMC) stimulated or not with Mycobacterium tuberculosis. Fluvastatin treatment resulted in the activation of caspase-1 and in a small secretion of interleukin (IL)-1beta, IL-18, and IFNgamma (Th1). In the presence of bacteria, the release of these cytokines was highly increased by the statin in a synergistic way. By contrast, production of IL-12, IL-10 and IL-4 were unaffected by the statin. Not only did mevalonate abolish the effects of the statin but it also prevented the caspase-1 activation induced by the bacteria, suggesting the involvement of isoprenoids in the response to M. tuberculosis. It is proposed that inhibition of HMG-CoA reductase may be immunoprotective by enhancing the Th1 response, which has therapeutical potential not only in atherosclerosis but also in infectious diseases.
Atherosclerosis 2000 Dec
PMID:Hydroxymethylglutaryl-coenzyme A reductase inhibition stimulates caspase-1 activity and Th1-cytokine release in peripheral blood mononuclear cells. 1116 19

Apoptosis is a cell suicide program characterized by distinct morphological (cell shrinkage, membrane blebbing, pyknosis, chromatin margination, denser cytoplasmic images) and biochemical (e.g., DNA fragmentation into distinct ladders; degradation of apoptotic markers such as PARP and nuclear lamins) features. It is involved in multiple physiological processes examplified by involution of mammary tissues, embryonic development, homeostatic maintenance of tissues and organs, and maturation of the immune system, as well as in many pathological conditions represented by neurologic degeneration (Alzeimer's disease), autoimmune and inflammatory diseases, etiology of atherosclerosis, AIDS, and oncogenesis and tumor progression. Numerous molecular entities have been shown to regulate the apoptotic process. This review provides a concise summary of the recent data on the role of oncogenes/tumor suppressor genes, cytokines and growth factors/growth factor receptors, intracellular signal transducers, cell cycle regulators, reactive oxygen species or other free radicals, extracellular matrix regulators/cell adhesion molecules, and specific endonucleases and cytoplasmic proteases (the ICE family proteins) in regulating cell survival and apoptosis. Elucidation of the molecular mechanisms regulating apoptosis bears tremendous impact on enhancing our understanding of many diseases inflicting the human beings and undoubtedly brings us hope for the cure of these diseases.
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PMID:Apoptosis: A Current Molecular Analysis. 1117 95

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.
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PMID:Interleukin-1 and related proteins in cardiovascular disease in adults and children. 1177 30

T lymphocytes localize within lesions of two diametrically opposed expressions of atherosclerosis: stenosis-producing plaques and ectasia-producing abdominal aortic aneurysm (AAA). T(H)1 immune responses appear to predominate in human stenotic lesions. However, little information exists regarding the nature of the T-cell infiltrate in AAAs. We demonstrate here that AAAs predominantly express T(H)2-associated cytokines and correspondingly lack mediators associated with the T(H)1 response as determined by Western blot and immunohistochemical analysis. In particular, aneurysmal tissue expressed interleukin (IL)-4, IL-5, and IL-10, cytokines not or only faintly detected in nondiseased tissue or stenotic atheroma. In contrast, AAAs contained low levels of the T(H)1 characteristic cytokines IL-2 and IL-15, which are amply expressed in stenotic lesions. Notably, stenotic lesions, but not AAAs, contained mature forms of the interferon-gamma-inducing cytokines IL-12 and IL-18 as well as the IL-18-processing enzyme caspase-1. Moreover, aneurysmal tissue lacked the receptor for interferon-gamma, although both types of lesions contained this T(H)1-promoting cytokine. These findings suggest that the functional repertoire of T cells differs in stenotic and aneurysmal lesions, and provide a novel framework for understanding the mechanisms of these diametrically opposite expressions of atherosclerosis.
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PMID:T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. 1216 75

Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared to cells derived from the adjacent media, and that in vitro expansion of LDC causes acquired resistance to apoptosis. Microarray profiling of fas-resistant versus sensitive cells identified a set of genes including STATs, caspase 1, cyclin D1, Bcl-xL, VDAC2, and BAD. The STAT proteins have been implicated in resistance to apoptosis, potentially via their ability to modulate caspase 1 (ICE), Bcl-xL, and cyclin D1 expression. Western blot analysis of sensitive and resistant LDC clonal lines confirmed increases in cyclin D1, STAT6, Bcl-xL, and BAD, with decreased expression of caspase 1. Thus, transcript profiling has identified a potential pathway of apoptotic regulation in subsets of lesion cells. The resistant phenotype may contribute to plaque stability and excessive vascular repair, while sensitive cells may be involved in plaque rupture and infarction. The data suggests both genetic interventions and novel small-molecule inhibitors that may be effective modulators of apoptosis in atherosclerosis, angina, and in-stent restenosis.
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PMID:Genomic profiling of acquired resistance to apoptosis in cells derived from human atherosclerotic lesions: potential role of STATs, cyclinD1, BAD, and Bcl-XL. 1600 68

In this review, 2 cytokines are discussed with respect to the inflammatory processes that are fundamental to aging and mortality. Both interleukin (IL)-1 and IL-18 are members of the same structural family (IL-1 family, or IL-F); there are presently 9 members of this family, but with the exception of IL-1alpha, IL-1beta, and IL-18, the others are antagonists or remain without known function. IL-1alpha is an intracellular cytokine with properties of both a cytokine and a transcription factor. IL-1beta and IL-18 are closely related; both possess a similar three-dimensional structure, and their respective precursor forms are inactive until cleaved by the intracellular cysteine protease caspase-1. Patients with mutations in the NALP3 gene, which controls the activity of caspase-1, readily secrete more IL-1beta and IL-18 and suffer from systemic inflammatory diseases. Patients with defects in this gene have high circulating concentrations of IL-6, serum amyloid A, and C-reactive protein, each of which decrease rapidly upon blockade of the IL-1 receptor, which suggests that IL-1beta contributes to the elevation of these markers of the inflammatory mechanisms of aging. Animal studies support the concept that IL-1beta and IL-18 participate in the pathogenesis of atherosclerosis. For example, overexpression of the IL-18 binding protein, a naturally occurring, specific inhibitor of IL-18, prevents the spontaneous development of atherosclerosis in apolipoprotein E-deficient mice. From human and animal studies, one may conclude that IL-1beta and IL-18 participate in fundamental inflammatory processes that increase during the aging process.
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PMID:Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. 1647 11

Recent findings suggest that the oxidative modification of low-density lipoproteins (LDL) and an increase in triglyceride-rich lipoprotein particles including chylomicron remnants contribute to the progression of atherosclerosis, as does the inflammatory response. We therefore examined whether and how these lipoproteins affected interleukin (IL)-1beta release and mRNA expression for IL-1beta and IL-18 in THP-1 cells, a human monocyte cell line. Chylomicron remnants increased IL-1beta release into the conditioned medium by THP-1 in a dose- and time-dependent manner. At concentrations up to 1 microg/ml, chylomicron remnants increased IL-1beta release by 4-fold compared with the control. Neither native LDL nor oxidized LDL (OxLDL) significantly increased IL-1beta release. Chylomicron remnants increased IL-1beta mRNA expression by 3 times. Native LDL or OxLDL did not increase IL-1beta mRNA, while neither these lipoproteins nor chylomicron remnants increased IL-18 mRNA. Chylomicron remnants also increased the activities of caspase-1 and nuclear factor (NF)-kappaB significantly, while native LDL or OxLDL did not. In conclusion, chylomicron remnants stimulated IL-1beta mRNA expression and IL-1beta protein production probably via caspase-1 and NF-kappaB activation in THP-1 cells.
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PMID:Chylomicron remnants stimulate release of interleukin-1beta by THP-1 cells. 1650 90


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