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:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to effectively use cynomolgus monkeys as animal models for human diseases, more than 300 anti-human monoclonal antibodies (mAbs) were studied as to their cross-reaction with various antigens from cynomolgus monkeys (Macaca fascicularis). Two hundred twenty-nine of 339 (67.55%) anti-human mAbs that react with human antigens of CD-defined molecules, chemokine receptors, and T cell receptors were cross-reactive with the monkey antigens. Using the cross-reactive antibodies and the fluorescenced beads for calibration, the procedure for the absolute count of monkey lymphocyte subsets was developed and the mean values for CD4+ and CD8+ lymphocyte subsets in peripheral blood were 718 and 573/mm3, respectively. Moreover, intracellular cytokines, IL-2, IL-4 and IFN gamma, and intracellular apoptosis-related proteins, Bcl-2, FADD and active form of caspase-3 could be detected in peripheral blood mononuclear cells as well as various tissue cells. It is therefore practicable to detail the phenotype of leukocytes, assess the production of intracellular cytokines and enumerate T-lymphocyte subsets by using the cross-reactive human antibodies with respective antigens of cynomolgus monkeys.
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PMID:Upgrading of flow cytometric analysis for absolute counts, cytokines and other antigenic molecules of cynomolgus monkeys (Macaca fascicularis) by using anti-human cross-reactive antibodies. 1088 48

Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1--50 microM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.
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PMID:Inhibition of neutrophil apoptosis by acrolein: a mechanism of tobacco-related lung disease? 1150 2

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA(4), 15-(R/S)-methyl-11,12-dehydro-LXA(4) methyl ester (15-(R/S)-methyl-LXA(4)), and stable analogs of LXA(4) on TNF-alpha-stimulated neutrophil-enterocyte interaction in vitro and TNF-alpha-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA(4), 15-(R/S)-epi-LXA(4), and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) inhibited TNF-alpha-stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA(4)potently attenuated TNF-alpha-stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-alpha induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(R/S)-methyl-LXA(4) attenuated TNF-alpha-stimulated colonocyte apoptosis and protected the mucosa against TNF-alpha-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-alpha-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-alpha-induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.
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PMID:Lipoxin A(4) and aspirin-triggered 15-epi-lipoxin A(4) antagonize TNF-alpha-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-alpha-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo. 1150 22

Depletion of CD4(+) T lymphocytes is a central immunological characteristic of HIV-1 infection. Although the mechanism of such CD4(+) cell loss following macrophage-tropic (R5) HIV-1 infection remains unclear, interactions between viral and host cell factors are thought to play an important role in the pathogenesis of HIV-1 disease. Based on the observation that TGF-beta1 enhanced expression of HIV chemokine coreceptors, the role of this host factor in virus effects was investigated using PBLs cultured in a nonmitogen-added system in the absence or presence of TGF-beta1. Most CD4 cells in such cultures had the phenotype CD25(-)CD69(-)DR(-)Ki67(-) and were CD45RO(bright)CD45RA(dim). Cultured cells had increased expression of CCR5 and CXCR4 and supported both HIV-1 entry and completion of viral reverse transcription. Virus production by cells cultured in the presence of IL-2 was inhibited by TGF-beta1, and this inhibition was accompanied by a loss of T cells from the culture and an increase in CD4(+) T cell apoptosis. Whereas R5X4 and X4 HIV-1 infection was sufficient to induce T cell apoptosis, R5 HIV-1 failed to induce apoptosis of PBLs in the absence of TGF-beta1 despite the fact that R5 HIV-1 depletes CD4(+) T cells in vivo. Increased apoptosis with HIV and TGF-beta1 was associated with reduced levels of Bcl-2 and increased expression of apoptosis-inducing factor, caspase-3, and cleavage of BID, c-IAP-1, and X-linked inhibitor of apoptosis. These results show that TGF-beta1 promotes depletion of CD4(+) T cells after R5 HIV-1 infection by inducing apoptosis and suggest that TGF-beta1 might contribute to the pathogenesis of HIV-1 infection in vivo.
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PMID:Synergistic induction of apoptosis in primary CD4(+) T cells by macrophage-tropic HIV-1 and TGF-beta1. 1154 26

Agonistic antibodies against the Fas receptor, when administered to mice in vivo, cause significant apoptosis in the liver. In this study we show that anti-Fas antibody not only causes apoptosis of liver cells but also provokes hepatic inflammation. Two hours after injection of anti-Fas, when mice displayed evidence of caspase-3 activation and apoptosis, we found significant hepatic induction of the CXC chemokines macrophage inflammatory protein-2 and KC. Coincident with the chemokine induction was infiltration of the hepatic parenchyma by neutrophils. Neutralization experiments identified that chemokines were the cause of Fas-induced hepatic inflammation, with KC having the predominant effect. Chemokine induction in the livers of anti-Fas-treated mice was not associated with activation of NF-kappa B. Instead, it coincided with nuclear translocation of activator protein-1 (AP-1). AP-1 activation in liver was detected 1-2 h after anti-Fas treatment, suggesting a connection to the onset of apoptosis. When apoptosis was prevented by pretreating mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced. Hepatic inflammation was also reduced by 70%. Taken together, these findings indicate that Fas ligation can induce inflammation in the liver in vivo. Inflammation does not arise from Fas-mediated signaling through NF-kappa B; rather, it represents an indirect effect, requiring activation of caspase-3 and nuclear translocation of AP-1.
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PMID:Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. 1160 13

Chemokine receptors are members of the G protein coupled receptor (GPCR) supergene family whose expression is highly restricted to hematopoietic cells. Although the primary role of chemokine and chemokine receptor interaction is believed to be regulation of chemotaxis of leukocytes, subsequent information clearly suggests that multiple immune regulatory functions are attributed to chemokine receptor signaling. We recently showed that activation of the CC chemokine 9 receptor (CCR9), a thymus-specific chemokine receptor, led to potent cFLIP(L)-independent resistance to cycloheximide-induced apoptosis and modest resistance to Fas-mediated apoptosis possibly via activation of multiple signaling components involving Akt and glycogen synthase kinase 3beta. The fact that these two apoptotic signals involve activation of similar arrays of death execution machinery such as caspase-8, caspase-9, or caspase-3, suggests that chemokine receptor signaling may provide a wide range of antiapoptotic activities to hematopoietic cells under certain biological conditions. GPCR is a large family of cell surface receptors, many of which are critically involved in hormonal and behavioral control. Recent observations also suggest that GPCR signaling plays a pivotal role in immune cell activation. Heterotrimeric G protein is an integral part of GPCR signaling. Thus, dissection of signaling components involved in the CCR9-mediated antiapoptosis could be a framework for cell survival mechanisms and may provide options for therapeutic interventions for neurdegenerative diseases or T cell malfunctioning.
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PMID:Role of the CC chemokine receptor 9/TECK interaction in apoptosis. 1199 71

The mechanisms regulating retrograde neuronal degeneration and subsequent death of thalamic neurons following cortical injury are not well understood. However, the delay in the onset of retrograde cell death and observed morphological changes are consistent with apoptosis. Our previous studies demonstrated that monocyte chemoattractant protein-1 (MCP-1), a beta-chemokine that attracts cells of monocytic origin to sites of injury, is rapidly and specifically expressed in the lateral geniculate nucleus following visual cortical lesions. To determine the potential role of MCP-1 in retrograde degeneration, the present study examined the effect of genetic deletion of MCP-1 (MCP-1 KO or -/-) or its high affinity receptor CCR2 (CCR2 KO or -/-) on thalamic microglial activation and neuronal cell death following aspiration lesions of the visual cortex in adult mice. Deletion of the MCP-1 gene delayed microglial activation and transiently improved the survival of thalamic neurons. Deletion of the CCR2 receptor resulted in a significant increase in apoptosis as measured by nucleosomal fragmentation after injury compared to wild-type mice, but did not alter neuron survival, suggesting that glial apoptosis is increased in the receptor knockout mice. Investigation of Bcl-2, Bax, Fas, Fas ligand (FasL) and activated caspase-3, key regulators of apoptosis that can be modulated by cytokines, revealed complex alterations of mRNA and protein levels in MCP-1(-/-) and CCR2(-/-) mice. As examples, Bcl-2 protein was detected in wild-type, but not in MCP-1(-/-) mice. Caspase-3 activity was higher in MCP-1(-/-) mice compared to wild-type and CCR2(-/-) mice at 5 days after injury. High levels of activated caspase-3 correlate with the beginning of a period of delayed, but rapid cell death in the thalami of MCP-1(-/-) mice. In summary, our data strongly suggest that MCP-1 is involved in early microglial response to axotomy and that modulation of this chemokine could provide a novel strategy for improved neuronal survival following injury to the central nervous system.
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PMID:Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. 1210 88

Ozone is known to be a highly toxic gas present in the urban air which exerts its effect on pulmonary tissue through its facile chemical reactions with target molecules in the airway. One of the first barriers encountered by ozone is epithelial lining fluid which contains pulmonary surfactant rich in glycerophosphocholine lipids. The reaction of ozone with calf lung surfactant extract was found to result in the production of 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (16:0a/9-al-GPCho) as an expected product of the ozonolysis of abundant unsaturated phospholipids containing unsaturated fatty acyl groups with a double bond at carbon-9. This oxidized phospholipid was identified as a biologically active product in that it reduced elicited macrophage viability by necrosis with an ED(50) of 6 microM. Further studies of the biological activity of 16:0a/9-al-GPCho revealed that concentrations from 100 to 200 nM initiated apoptosis in pulmonary epithelial-like A549 cells as assessed by TUNEL staining, nuclear size, and caspase-3 activation with loss of viability indicated by reduction of mitochondrial dehydrogenase activity. The release of IL-8, a neutrophil chemokine, from A549 cells was also stimulated by 50-100 nM 16:0a/9-al-GPCho. Exposure of calf lung surfactant to low levels of ozone (62.5, 125, and 250 ppb) for various time periods from 2 to 48 h in a feedback-regulated ozone exposure chamber resulted in a dose- and time-dependent increase in the formation of 16:0a/9-al-GPCho as measured by a specific and sensitive LC/MS/MS assay. The quantity of this biologically active chain-shortened glycerophosphocholine lipid generated even at 125 ppb ozone for 2-4 h (50-100 nM) was consistent with this product mediating the toxic effects of ozone on cells in contact with surfactant.
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PMID:Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability. 1211 99

Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.
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PMID:Age-dependent resistance to lethal alphavirus encephalitis in mice: analysis of gene expression in the central nervous system and identification of a novel interferon-inducible protective gene, mouse ISG12. 1238 28

Mediators of lymphocyte infiltration in inflammatory thyroid disease have yet to be identified. Here we examine the ability of IL-1beta to enhance the production of chemoattractants by human thyrocytes. Primary cultures, when treated with the cytokine, release T lymphocyte chemotactic activity. The effect of IL-1beta is time dependent, and the chemoattraction activity can be partially attenuated by the addition of either anti-IL-16 or anti-regulated upon activation, normal T cell expressed, and secreted (RANTES) neutralizing antibodies. IL-16 is a CD4(+)-specific ligand, and RANTES is a C-C type chemokine that targets monocytes and lymphocytes. These chemoattractants could be detected by specific ELISAs in conditioned medium from IL-1beta treated thyrocytes. Northern analysis revealed that thyrocytes express high constitutive levels of IL-16 mRNA, which were invariant with regard to IL-1beta (10 ng/ml) or glucocorticoid treatment. RANTES mRNA was not detected in control cultures but was strongly induced by the cytokine. IL-16 but not RANTES expression was dependent on the activity of caspase-3. Pro-IL-16 protein could be detected in homogenates of thyroid tissue from patients with multinodular goiter and Graves' disease. Thus, human thyrocytes, through the expression of chemoattractants, may participate in the recruitment of lymphocytes to the thyroid in inflammatory states.
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PMID:Cytokine-induced lymphocyte chemoattraction from cultured human thyrocytes: evidence for interleukin-16 and regulated upon activation, normal T cell expressed, and secreted expression. 1281 May 40


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