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)

We have recently observed that inhibition of NF-kappaB in NIT-1 insulinoma cells protects them from tumour necrosis factor (TNF)-induced cell death in vitro, possibly because expression of interleukin-1 (IL-1)beta-converting enzyme (ICE), a member of the cysteine protease pathway of cell death, is decreased. In the current study we have examined the effect of the same inhibitor of NF-kappaB on class I major histocompatibility complex (MHC) protein expression in NIT-1 cells and shown that inhibition of NF-kappaB activation decreased basal and TNF-induced class I MHC levels. Although inducible nitric oxide synthase (iNOS) may also be inhibited by inhibition of NF-kappaB, this could not be demonstrated in NIT-1/delta sp cells because wild-type NIT-1 cells express very little iNOS. When NIT-1/delta sp12 cells, expressing high levels of the NF-kappaB inhibitor, are transplanted into immunodeficient NOD/scid mice, tumorigenesis and death by hypoglycemia proceed similarly to untransfected NIT-1 cells. Untransfected NIT-1 cells were killed by co-transfer of splenic T cells from diabetic but not non-diabetic NOD mice. NIT-1/delta sp12 cells were protected from killing in vivo by T cells from diabetic mice, in that tumours developed in four out of five mice and the kinetics of tumour development were not significantly delayed. NIT-1/delta sp12 cells were not protected from killing by T cells from mice previously primed with NIT-1 cells. In conclusion, inhibition of NF-kappaB is likely to suppress several different pathways of immune-mediated cell death in beta-cells and protects NIT-1 cells from immune attack by diabetogenic T cells in vivo. Inhibition of NF-kappaB is a potentially effective strategy for protection of pancreatic beta-cells in autoimmune diabetes.
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PMID:Protection of NIT-1 pancreatic beta-cells from immune attack by inhibition of NF-kappaB. 921 57

Overproduction of proinflammatory cytokines in the brains of transgenic animals causes brain pathology. To investigate the relationship between brain cytokines and pathology in the brains of animals with adult-onset, pathophysiologically induced brain cytokine expression, we studied rats infected with the parasite Trypanosoma brucei. Several weeks after infection, in situ hybridization histochemistry showed a pattern of chronic overexpression of the mRNAs for proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha in the brains of the animals. Similar spatiotemporal inductions of mRNAs for inhibitory factor kappaBalpha and interleukin-1beta converting enzyme were found and quantified. The mRNAs for inducible nitric oxide synthase and interleukin-1 receptor antagonist were highly localized to the choroid plexus, which showed evidence of structural abnormalities associated with the parasites' presence there. The mRNAs for interleukin-6, interferon-gamma, and inducible cyclooxygenase showed restricted induction patterns. Another set of animals was processed for degeneration-induced silver staining, TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining, glial fibrillary acidic protein (GFAP) immunohistochemistry, and several other histological markers. Apoptosis of scattered small cells and degeneration of certain nerve fibers was found in patterns spatially related to the cytokine mRNA patterns and to cerebrospinal fluid diffusion pathways. Furthermore, striking cytoarchitectonically defined clusters of degenerating non-neuronal cells, probably astrocytes, were found. The results reveal chronic overexpression of potentially cytotoxic cytokines in the brain and selective histopathology patterns in this natural disease model. J. Comp. Neurol. 414:114-130, 1999. Published 1999 Wiley-Liss, Inc.
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PMID:Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with Trypanosoma brucei. 1049 82

We have reported previously that axonal degeneration in specific brain regions occurs in rats infected with the parasite Trypanosoma brucei. These degenerative changes occur in spatiotemporal association with over-expression of pro-inflammatory cytokine messenger RNAs in the brain. To test how aspirin-like anti-inflammatory drugs might alter the disease process, we fed trypanosome-infected rats with 200mg/kg of sodium salicylate (the first metabolite of aspirin) daily in their drinking water. Sodium salicylate treatment in uninfected rats did not cause any neural damage. However, sodium salicylate treatment greatly exacerbated neurodegeneration in trypanosome-infected rats, resulting in extensive terminal and neuronal cell body degeneration in the cortex, hippocampus, striatum, thalamus, and anterior olfactory nucleus. The exaggerated neurodegeneration, which occurred in late stages of infection, was temporally and somewhat spatially associated with a late-appearing enhancement of messenger RNA expression of interleukin-1beta, interleukin-1beta converting enzyme, tumor necrosis factor-alpha, and inhibitory factor kappaBalpha in the brain parenchyma. Restricted areas showed elevations in messenger RNA expression of interleukin-1 receptor antagonist, interleukin-6, inducible nitric oxide synthase, interferon-gamma, and inducible cyclooxygenase. The association suggests that increased production of pro-inflammatory cytokines in the brain may be an underlying mechanism for neural damage induced by the chronic sodium salicylate treatment. Furthermore, the results reveal a serious complication in using aspirin-like drugs for the treatment of trypanosome infection.
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PMID:Chronic sodium salicylate treatment exacerbates brain neurodegeneration in rats infected with Trypanosoma brucei. 1068 22

Whereas nitric oxide (NO) production is associated with the toxic effect of cytokines on rodent pancreatic beta-cells, cytokine-induced apoptosis in human islets may occur independently of NO. The cysteine protease interleukin (IL)-1 converting enzyme (ICE) is a key proapoptotic caspase. Our aim was therefore to analyze the effect of cytokines on ICE expression in human, rat, and mouse islets and rat insulinoma cells. ICE messenger RNA (mRNA) expression was highly up-regulated after 6-, 24-, and 72-h exposure of human islets to interferon (IFN)gamma, tumor necrosis factor (TNF)alpha + IFNgamma or IL-1beta + TNFalpha + IFNgamma, paralleled by increased iNOS (the inducible form of NO synthase) expression and NO production after exposure to the combined cytokines but not to IFNgamma or TNFalpha + IFNgamma. Cytokine-induced NO-independent ICE transcription was confirmed using iNOS inhibitors. Exposure of rat and mouse islets, or rat insulinoma cells, for 24 h to IFNgamma alone or in combination with the two other cytokines also resulted in a highly significant ICE mRNA expression. ICE transcription was not inducible in islets from IFN regulatory factor-1 knock-out mice, suggesting a key-role of this transcription-factor in cytokine-mediated ICE expression in pancreatic islets. In conclusion, cytokines and IFNgamma in particular increase ICE mRNA expression in pancreatic islet cells and beta-cell lines, independently of NO synthesis, suggesting that ICE up-regulation may be involved in cytokine-induced NO-independent apoptosis of human islets.
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PMID:Interferon-gamma induces interleukin-1 converting enzyme expression in pancreatic islets by an interferon regulatory factor-1-dependent mechanism. 1069 Aug 98

The role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice, and caused a significant mortality (62%) only in the latter mice, indicating that interleukin-6 deficiency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75mg/kg kainic acid and were killed six days later. Morphological damage to the hippocampal field CA1-CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitrite-induced nitration of proteins and byproducts of fatty acid peroxidation were dramatically increased, as was that for metallothionein I+II, Mn-superoxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a significant neuronal apoptosis was caused by kainic acid, as revealed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and interleukin-1beta converting enzyme/Caspase-1 stainings. In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and microgliosis were reduced, while morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I+II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death in the interleukin-6 null mice. The present results demonstrate that interleukin-6 deficiency increases neuronal injury and impairs the inflammatory response after kainic acid-induced seizures.
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PMID:Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures. 1118 44

The role of endogenous NO on cell survival was investigated in human melanoma cells and melanocytes. Inducible NO synthase (iNOS) was always expressed in a panel of melanoma cell lines from metastatic lesions and in normal adult melanocytes. iNOS was also detected by immunohistochemistry in melanoma cells from metastases. Release of NO by tumor cells and melanocytes was inhibited by a specific iNOS inhibitor, aminoguanidine (AMG). Inhibition of endogenous NO synthesis did not affect cell cycle progression of melanoma cells but led to cell death by apoptosis, as indicated by Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. By contrast, iNOS inhibition by AMG did not promote apoptosis in normal adult melanocytes. A mitochondrial pathway was involved in melanoma apop tosis, as indicated by altered mitochondrial membrane potential (delta psi(m)) and down-regulation of Bcl-2 protein level after iNOS inhibition. AMG treatment triggered release of caspase-1, enzymatic activation of caspase-3, and degradation of poly(ADP-ribose) polymerase, one of the main caspase-3 substrates. Melanoma cell apoptosis induced by iNOS inhibition was completely blocked by peptide inhibitors of caspase-1 and caspase-3 (Ac-DEVD-CHO and AC-YVAD-CHO) or by an exogenous NO donor, sodium nitroprusside, or by addition of serum. Finally, comparison of control and AMG-treated melanoma cells by pathway-specific gene array analysis indicated that inhibition of NO synthesis led, before induction of apoptosis, to up-regulation of mRNA levels of genes involved in the apoptosis pathway such as Bax, caspase-1, caspase-3, caspase-6, gadd45beta, mdm2, and TRAIL. Taken together, these results indicate that melanoma cell survival is regulated by endogenous NO resulting from iNOS activity.
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PMID:Antiapoptotic role of endogenous nitric oxide in human melanoma cells. 1119 80

Inflammatory cytokines and enzymes such as IL-1 and inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of AIDS dementia, a condition associated with infection of the CNS cells by the HIV-1. In this report, we investigated the expression of iNOS, IL-1, and caspase-1 (interleukin-1 converting enzyme) in HIV-1 encephalitis (HIVE) by immunocytochemistry and analyzed their expression with respect to HIV-1 infection and glial activation. In HIVE, all three molecules were expressed at high levels in areas of HIV-1 infection (microglial nodules with HIV-1 p24 immunoreactivity) and in areas of diffuse white matter gliosis. Expression was cell-type specific, with IL-1 and caspase-1 being expressed in macrophages and microglia, and iNOS in activated astrocytes. Multinucleated giant cells, a hallmark of virally infected cells, showed intense staining for both IL-1 and caspase-1, suggesting induction of these molecules by HIV-1. Double immunocytochemistry demonstrated a regional co-localization of astrocyte iNOS and microglial IL-1 and caspase-1. These results support the notion that autocrine and paracrine interactions between HIV-1 infected macrophages and microglia, activated microglia, and astrocytes lead to expression of proinflammatory and neurotoxic molecules. iNOS and caspase-1 may provide additional therapeutic targets for HIVE.
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PMID:Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis. 1128 69

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated Cu2+/Zn2+ superoxide dismutase 1. HGF prevented induction of caspase-1 and inducible nitric oxide synthase (iNOS) in motoneurons and retained the levels of the glial-specific glutamate transporter (excitatory amino acid transporter 2/glutamate transporter 1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.
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PMID:Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. 1215 33

We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.
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PMID:A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays. 1250 44


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