Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalidomide has been shown to be an effective treatment in various immunologic diseases such as Crohn's disease and rheumatoid arthritis. Its major effect is thought to be mediated by the inhibition of TNF-alpha, but the exact mechanism of action is still uncertain. Recent observations could demonstrate that the induction of monocyte apoptosis is a common feature of a variety of anti-inflammatory agents. Therefore, we investigated the role of thalidomide on monocyte apoptosis. Treatment with thalidomide resulted in apoptosis of human peripheral blood monocytes in a time- and dose-dependent manner as demonstrated by annexin V staining. Monocyte apoptosis required the activation of caspases, as combined stimulation by thalidomide together with the broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone markedly prevented monocyte cell death. Apoptosis was triggered by a CD95/CD95 ligand, TNF-RI, and TRAIL-R1 independent pathway with an inhibition of AKT-1 kinase and consecutive mitochondrial release of cytochrome c, followed by the proteolytic activation of initiator caspase-9 and effector caspase-3. Our data suggest that thalidomide-induced monocyte apoptosis is at least partially mediated by a mitochondrial signaling pathway and might contribute to the complex immunomodulatory properties of the drug.
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PMID:Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway. 1506 94

Tumor necrosis factor (TNF)-alpha is implicated in development of restenotic and atherosclerotic vascular lesions, which are pathological processes involving both proliferation and apoptosis of vascular smooth muscle cells (VSMCs). Human VSMCs were recently found to contain heterogeneous subpopulations. We therefore examined whether TNF has different effects on distinct subpopulations of VSMCs. With the use of cloning techniques, two stable subpopulations of VSMCs were isolated from human saphenous vein: spindle- and epithelioid-shaped smooth muscle cells (Sp- and Ep-SMCs, respectively). We found that TNF stimulated growth in Sp-SMCs but had a toxic effect on Ep-SMCs. TNF did not induce apoptosis in Sp-SMCs as determined by nuclear staining and cellular DNA electrophoresis. In contrast, the reduction of viability in Ep-SMCs was associated with induction of apoptosis as characterized by cellular DNA fragmentation and nuclear condensation. Higher levels of the TNF-R1 receptor subtype were detected in membrane preparations from Ep-SMCs than in membranes from Sp-SMCs. Activation of caspase-3 was also selectively induced in Ep-SMCs but not in Sp-SMCs. Cycloheximide, an inhibitor of protein synthesis, enhanced the toxicity of TNF in Ep-SMCs. This effect of cycloheximide was not seen in Sp-SMCs. The data presented here demonstrate for the first time that TNF either promotes growth or induces apoptosis in human VSMCs depending on phenotype.
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PMID:TNF-alpha induces proliferation or apoptosis in human saphenous vein smooth muscle cells depending on phenotype. 1535 8

Tumor necrosis factor-alpha (TNF-a) is produced by alveolar macrophages (AM) in response to bleomycin (BLM) exposure. This cytokine has been linked to BLM-induced pulmonary inflammation, an early drug effect, and to lung fibrosis, the ultimate toxic effect of BLM. The present study was carried out to study the time dependence of apoptotic signaling pathways and the potential roles of TNF receptors in BLM-induced AM apoptosis. Male Sprague-Dawley rats were exposed to saline or BLM (1 mg/kg) by intratracheal instillation. At 1, 3, or 7 d postexposure, AM were isolated by bronchoalveolar (BAL) lavage and evaluated for apoptosis by ELISA. The release of cytochrome c from mitochrondria, the activation of caspase-3, -8, and -9, the cleavage of nuclear poly(ADP-ribose) polymerase (PARP), and the expression of TNF receptors (TNF-R1/p55 and TNF-R2/p75), TNF-R-associated factor 2 (TRAF2), and cellular inhibitor of apoptosis 1 (c-IAP1) were determined by immunoblotting. The results showed that BLM exposure induced AM apoptosis, with the highest apoptotic effect occurring at 1 d after exposure and gradually decreasing at 3 and 7 d postexposure, but still remaining significantly above the control level. The maximal translocation of cytochromec from mitochondria into the cytosol was observed at 1 d postexposure, whereas the activation of caspase-9 and caspase-3 and caspase-3-dependent cleavage of PARP was found to reach a peak level at 3 d postexposure. BLM exposure had no marked effect on AM expression of TNF-R1 or caspase-8 activation, but significantly increased the expression of TNF-R2 that was accompanied by a rise in c-IAP1 and a decrease in TRAF2. This induction of TNF-R2 by BLM was significant on d 1 and increased with greater exposure time. In vitro studies showed that pretreatment of naive AM with a TNF-R2 antibody significantly inhibited BLM-induced caspase-3 activity and apoptosis. These results suggest that BLM-induced apoptosis involves multiple pathways in a time-dependent manner. Since maximal BLM-induced AM apoptosis (1 d postexposure) preceded maximal changes in caspase-9 and -3 (3 d postexposure), it is possible that a caspase-independent mechanism is involved in this initial response. These results indicate that the sustained expression of TNF-R2 in AM by BLM exposure may sensitize these cells to TNF-a-mediated toxicity.
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PMID:Time-dependent apoptosis of alveolar macrophages from rats exposed to bleomycin: involvement of tnf receptor 2. 1537 Dec 38

The Notch signaling pathway plays an important role in the regulation of self-renewal and differentiation of hematopoietic progenitors. Tumor necrosis factor (TNF)-alpha induces apoptosis through activation of caspase pathway. A monoblastic leukemia cell line, U937, undergoes apoptosis following stimulation with TNF-alpha. We found that Notch activation induced by a recombinant Notch ligand, Delta-1, reduced the TNF-alpha-induced growth suppression and apoptosis in U937 cells. As the molecular mechanism involved, we showed Delta-1 stimulation partially suppressed the sequential activation of caspase-8, caspase-3, and, PARP induced by TNF-alpha. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK), p38, and NF-kappaB was not affected by Delta-1 stimulation. The cells needed to be exposed to Delta-1 prior to TNF-alpha stimulation to reduce the suppressive effect of TNF-alpha. Therefore, we thought that Delta-1 stimulation might reduce the expression of TNF-receptor (R) 1 and proteins to modulate the activation of caspases such as FLIP and XIAP. However, Delta-1 stimulation did not affect their expression. The precise mechanism by which Notch signaling suppresses caspase activation has yet to be determined. This is the first report to show the relationship between Notch activation and TNF-R1 signaling. The findings suggest possible mechanisms by which Notch activation supports cell survival.
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PMID:The Notch ligand, Delta-1, reduces TNF-alpha-induced growth suppression and apoptosis by decreasing activation of caspases in U937 cells. 1549 57

Tumor necrosis factor (TNF) receptors (TNF-R)-mediated cell survival or apoptosis has been demonstrated in many cells, but little is known about survival or apoptotic signals via TNF-R1 in tendinocytes. In this study, we focused on four signaling factors, TNFalpha, TNF-R1, TNFR-associated factor2 (TRAF2) and caspase-3, in order to elucidate the signaling events in tendinocytes. Samples were obtained from normal, inflamed and scar-formed equine superficial digital flexor tendons. To detect these signaling factors, samples were subjected to immunohistochemistry and Western blot analysis, and some samples were also subjected to reverse transcription-polymerase chain reaction (RT-PCR), PCR-Southern blot analysis and in situ hybridization to detect the expression of TNFalpha mRNA. Distribution of the four factors differed depending on the tendon condition, normal, inflamed or scar-formed. In the normal tendon, large amounts of TRAF2 were found in tendinocytes, but the amounts of TNF-R1 were small. TNFalpha mRNA was expressed most highly in the inflamed tendon. TNF-R1, which was only faintly detected in the normal tendon, was detected at a high level in the inflamed tendon, and the amounts of TRAF2 and caspase-3 also increased. Activated caspase-3 was only detected in the inflamed tendon. TNFalpha mRNA was also expressed in the scar-formed tendon, though it showed weak signals, and the expression levels of TNF-R1, TRAF2 and caspase-3 proteins were very low. Two distinct intracellular signaling pathways of TNFalpha, which lead to cell survival and apoptosis, might be present in tendinocytes mediated through TNF-R1. These results, which reflect the dynamism of TNFalpha, provide important clues for means to prevent tendinopathy.
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PMID:Differences in tumor necrosis factor (TNF)alpha and TNF receptor-1-mediated intracellular signaling factors in normal, inflamed and scar-formed horse tendons. 1627 53

Melanoma is an intractable tumor that has shown very impressive and promising response to local administration of high dose recombinant TNF-alpha in combination with IFN-gamma in clinical studies. In this study, we investigated the effect of IL-6/sIL-6R on TNF-alpha-resistant B16/F10.9 melanoma cells. A low dose of TNF-alpha or IL-6/sIL-6R had minimal affect on the cell growth. However, the highly active fusion protein of sIL-6R and IL-6 (IL6RIL6), covalently linked by a flexible peptide, sensitized TNF-alpha-resistant F10.9 melanoma cells to TNF-alpha-induced apoptosis. Stimulation of the cells with IL6RIL6 plus TNF-alpha resulted in both the activation of caspase-3 and the reduction of bcl-2 expression. Flow cytometry analysis showed that IL6RIL6-upregulated TNF-R55 and TNF-R75 expression, suggesting an increase in TNF-alpha responsiveness by IL6RIL6 resulting from the induction of TNF receptors. Moreover, exposure of F10.9 cells to neutralizing antibody to TNF-R55 significantly inhibited IL6RIL6/TNF-alpha-induced cytotoxicity. These results suggest that the IL6/sIL6R/gp130 system, which sensitizes TNF-alpha-resistant melanoma cells to TNF-alpha-induced apoptosis, may provide a new target for immunotherapy.
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PMID:The IL-6/sIL-6R treatment of a malignant melanoma cell line enhances susceptibility to TNF-alpha-induced apoptosis. 1727 48

Control of apoptosis via death ligands plays a basic role for lymphocyte homeostasis and lymphoma development. In this study, cutaneous T-cell lymphoma (CTCL) cell lines revealed pronounced resistance to death ligands as compared to cell lines of T-cell acute lymphoblastic leukemia (T-ALL). The proapoptotic activity of tumor necrosis factor (TNF)-alpha was blocked, sensitivity to TNF-related apoptosis-inducing ligand was significantly reduced, and 1/4 CTCL cell lines was resistant to CD95 activation. In parallel, there was no activation of effector caspase-3 and initiator caspase-8 in nonresponsive CTCL cells, whereas caspase-10 was cleaved selectively in sensitive CTCL cells. No indication for a responsibility of typical downstream regulators of apoptosis was obtained, but loss of CD95 was found in 1/4, loss of TNF-R1 in 3/4, loss of caspase-10 in 2/4, loss of Bid in 1/4, and overexpression of cellular flice inhibitory protein was found in 4/4 CTCL cell lines. This clearly indicates an inhibition of apoptosis early in the extrinsic cascade, namely at the formation of the death-inducing signaling complex. Parallels with regard to expression of apoptosis regulators were seen in peripheral blood mononuclear cells and biopsies of CTCL patients. This study may indicate defects in apoptosis in CTCL and may help to guide CTCL therapy.
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PMID:Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells. 1749 57

Deficiency in cellular thiol tripeptide glutathione (L-gamma glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle.
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PMID:Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats. 1770 97

Human pancreatic tumor cells are highly resistant to both tumor necrosis factor (TNF) and to chemotherapeutic agents. HER-2/neu expression has been proposed as a negative prognostic marker in pancreatic intraepithelial neoplasia. Our approach was to utilize HER-2/neu expression on the surface of tumor cells as a therapeutic target employing scFv23/TNF, immunocytokine composed of a single chain Fv antibody (scFv23) targeting the HER-2/neu and the cytokine TNF as the cytotoxic moiety, to deliver TNF directly to TNF-resistant pancreatic tumor cells. Using a panel of human pancreatic cell lines, which overexpress HER-2/neu, we evaluated the in vitro response of cells to TNF, scFv23/TNF, Herceptin, and a combination of scFv23/TNF with various chemotherapeutic agents. We found that all pancreatic cancer cell lines were highly resistant to the cytotoxic effects of TNF and that scFv23/TNF was highly cytotoxic to TNF-resistant HER-2/neu-expressing pancreatic cancer cell lines at levels rivaling that of conventional chemotherapeutic agents. Combination studies demonstrated a synergistic cytotoxic effect of scFv23/TNF with 5-fluorouracil (5-FU) in TNF-resistant pancreatic cancer cell lines. Mechanistic studies demonstrated that the 5-FU plus scFv23/TNF combination specifically resulted in a down-regulation of HER-2/neu, p-Akt and Bcl-2 and up-regulation of TNF-R1. In addition, the combination 5-FU plus scFv23/TNF induced apoptosis and this synergistic effect was dependent on activation of caspase-8 and caspase-3. Delivery of the cytokine TNF to HER-2/neu expressing pancreatic tumor cells, which are inherently resistant to TNF using scFv23/TNF may be an effective therapy for pancreatic cancer especially when utilized in combination with 5-FU.
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PMID:The immunocytokine scFv23/TNF targeting HER-2/neu induces synergistic cytotoxic effects with 5-fluorouracil in TNF-resistant pancreatic cancer cell lines. 1808 72

Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.
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PMID:Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure. 1837 24


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