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)

Alzheimer's disease is marked by progressive accumulation of amyloid beta-peptide (Abeta) which appears to trigger neurotoxic and inflammatory cascades. Substantial activation of microglia as part of a local innate immune response is prominent at sites of Abeta plaques in the CNS. However, the role of activated microglia as Abeta APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Abeta-Ag presentation and interaction with Abeta-specific T cells. We found that IFN-gamma-treated microglia serve as efficient Abeta APCs of both Abeta1-40 and Abeta1-42, mediating CD86-dependent proliferation of Abeta-reactive T cells. When cultured with Th1 and Th2 subsets of Abeta-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-gamma, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Abeta-reactive Th2 cells was associated with expression of the Th2 cytokines IL-4 and IL-10, which counterbalanced the toxic levels of NO induced by Abeta. Our results demonstrate NO-dependent apoptosis of T cells by Abeta-stimulated microglia which may enhance CNS innate immune responses and neurotoxicity in Alzheimer's disease. Secretion of NO by stimulated microglia may underlie a more general pathway of T cell death in the CNS seen in neurodegenerative diseases. Furthermore, Th2 type T cell responses may have a beneficial effect on this process by down-regulation of NO and the proinflammatory environment.
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PMID:Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. 1292 65

Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro- and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13-16(14del)), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13-16(neg)) was correlated to a decreased B-CLL cell viability. The 9-beta-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13-16(neg) transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13-16(pos)), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide (.- NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.
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PMID:Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions. 1457 28

Lipopolysaccharide (LPS) exerts a myriad of effects in rat hippocampus; it increases the concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta), and signalling via the IL-1 type I receptor (IL-1RI) resulting in phosphorylation of the stress-activated protein kinase, c-jun-N-terminal kinase (JNK) and impairment in long-term potentiation (LTP). This study was designed to establish whether activation of JNK is a pivotal event in mediating the effects of LPS in hippocampus and therefore LPS-treated rats were injected intracerebroventricularly with saline, the JNK inhibitor D-JNKI1, or with the anti-inflammatory cytokine IL-4, which antagonizes the effects of IL-1beta upstream of JNK activation. We report that IL-4 blocked the LPS-induced increase in IL-1RI expression and associated increases in phosphorylation of JNK and c-jun, whereas D-JNKI1 inhibited the LPS-induced phosphorylation of c-jun. Both IL-4 and D-JNKI1 inhibited the increase in caspase-3 staining which was associated with LPS treatment, and both abrogated the LPS-induced inhibition of LTP in perforant path-granule cell synapses. The data presented are consistent with the proposal that JNK activation, probably as a result of increased IL-1RI activation, is a critical step in mediating the detrimental effects of LPS in hippocampus.
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PMID:Activation of c-Jun-N-terminal kinase is critical in mediating lipopolysaccharide-induced changes in the rat hippocampus. 1577 21

Extracellular ATP and other nucleotides act through specific cell surface receptors and regulate a wide variety of cellular responses in many cell types and tissues. In this study, we demonstrate that murine mast cells express several P2Y and P2X receptor subtypes including P2X(7), and describe functional responses of these cells to extracellular ATP. Stimulation of bone marrow-derived mast cells (BMMC), as well as MC/9 and P815 mast cell lines with millimolar concentrations of ATP, resulted in Ca(2+) influx across the cellular membrane and cell permeabilization. Moreover, brief exposures to ATP were sufficient to induce apoptosis in BMMCs, MC/9, and P815 cells which involved activation of caspase-3 and -8. However, in the time period between commitment to apoptosis and actual cell death, ATP triggered rapid but transient phosphorylation of multiple signaling molecules in BMMCs and MC/9 cells, including ERK, Jak2, and STAT6. In addition, ATP stimulation enhanced the expression of several proinflammatory cytokines, such as IL-4, IL-6, IL-13, and TNF-alpha. The effects of ATP were mimicked by submillimolar concentrations of 3-O-(4'-benzoyl)-benzoyl-benzoyl-ATP, and were inhibited by pretreatment of mast cells with a selective blocker of human and mouse P2X(7) receptor, 1[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine, as well as oxidized ATP. The nucleotide selectivity and pharmacological profile data support the role for P2X(7) receptor as the mediator of the ATP-induced responses. Given the importance of mast cells in diverse pathological conditions, the ability of extracellular ATP to induce the P2X(7)-mediated apoptosis in these cells may facilitate the development of new strategies to modulate mast cell activities.
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PMID:Extracellular ATP induces cytokine expression and apoptosis through P2X7 receptor in murine mast cells. 2128 17

NKT cells expressing phenotypic markers of both T and NK cells seem to be pivotal in murine models of immune-mediated liver injury, e.g., in Con A-induced hepatitis. Also alpha-galactosylceramide (alpha-GalCer), a specific ligand for invariant Valpha14 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of alpha-GalCer-induced hepatitis in mice. Liver injury induced by alpha-GalCer injection into C57BL/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. alpha-GalCer injection also induces pronounced cytokine responses, including TNF-alpha, IFN-gamma, IL-2, IL-4, and IL-6. We provide a detailed time course for the expression of these cytokines, both in liver and plasma. Cytokine neutralization revealed that, unlike Con A-induced hepatitis, IFN-gamma is not only dispensable for alpha-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-alpha was clearly identified as an important mediator for hepatic injury in this model that increased Fas ligand expression on NKT cells. Whereas intrahepatic Kupffer cells are known as a pivotal source for TNF-alpha in Con A-induced hepatitis, they were nonessential for alpha-GalCer-mediated hepatotoxicity. In alpha-GalCer-treated mice, TNF-alpha was produced by intrahepatic lymphocytes, in particular NKT cells. BALB/c mice were significantly less susceptible to alpha-GalCer-induced liver injury than C57BL/6 mice, in particular upon pretreatment with d-galactosamine, a hepatocyte-specific sensitizer to TNF-alpha-mediated injury. Finally, we demonstrate resemblance of murine alpha-GalCer-induced hepatitis to human autoimmune-like liver disorders. The particular features of this model compared with other immune-mediated hepatitis models may enhance comprehension of basic mechanisms in the etiopathogenesis of NKT cell-comprising liver disorders.
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PMID:Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells. 1603 92

Ischaemia-reperfusion injury is associated with an inflammatory response as well as apoptosis in the affected area. Inflammatory responses are characterized, among others, by an increased production of several cytokines, while caspases are implicated in the control of apoptosis. The aim of the present work was to determine changes in the levels of inflammatory and apoptotic indices in the rat brain after cerebral ischaemia-reperfusion and to evaluate the effect of the non-steroidal anti-inflammatory compound N-(2-thiolethyl)-2-{2-[N'-[2,6-dichlorophenyl)aminolphenyl} acetamide on these indices. A cerebral ischaemia-reperfusion rodent model was used to investigate, via immunohistochemical and colorimetric techniques, the presence in the brain and spleen of inflammatory enzymes cycloxygenases COX-1 and COX-2, cytokines interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-18, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) as well as the activated form of caspase-3, in treated and untreated animals. Cerebral ischaemia-reperfusion caused elevated levels in the rat post ischaemia. Treatment with the antiinflammatory derivative reduced the elevation, caused by ischaemia, of IFN-gamma, TNF-alpha, IL-1beta IL-6, IL-18 and caspase-3 levels at 3 days post ischaemia, while it increased the levels of IL-10. It was shown that the increase in concentrations of a wide range of cytokines involved in the inflammatory reaction causing brain damage after ischaemia-reperfusion can be partially reversed by the anti-inflammatory derivative used in this study.
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PMID:Effects of the novel non-steroidal anti-inflammatory compound [N-(2-thiolethyl)-2- {2- [N'- (2,6- dichlorophenyl) amino] phenyl}acetamide on cytokines and apoptosis in ischaemic rat brain. 1722 64

Data concerning T helper cell phenotypes in response to Mycobacterium tuberculosis infection remain controversial. T lymphocyte intracellular interleukin-4 production in response to CD3 stimulation was determined by flow cytometry in 21 TB patients and 14 community controls. In supplementary experiments the association of interleukin-4 expression with apoptosis was investigated. A low percentage of CD4 T cells in both patients and controls expressed high levels of interleukin-4 (IL-4(high)). A larger subset of both CD4 and CD8 T cells of all subjects expressed low levels of intracellular IL-4 (IL-4(low)). Stimulated and unstimulated cells expressed IL-4(low) and IL-4(high). IL-4(low) percentages were lower in TB patients at diagnosis compared to controls while IL-4(high) percentages were higher in patients. Most IL-4(high) cells co-expressed active caspase-3, a marker for apoptosis. This co-expression was also shown in experimentally induced apoptotic Jurkat cells and peripheral blood neutrophils and monocytes. IL-4 levels may therefore not necessarily indicate a skewed Th cell phenotype, as our data suggest that IL-4 production by CD4 and CD8 T cells can occur constitutively in healthy controls with latent TB infection and in TB patients. Cellular IL-4 production may represent a normal cellular growth factor mechanism which is disturbed at the onset of apoptosis.
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PMID:High levels of intracellular IL-4 are expressed in circulating apoptotic T cells in patients with tuberculosis and in community controls. 1797 94

After emigration from the bone marrow to the peripheral blood, monocytes enter tissues and differentiate into macrophages, the prototype scavenger of the immune system. By ingesting and killing microorganisms and removing cellular debris, macrophages also process antigens as a first step in mounting a specific immune response. IL-32 is a cytokine inducing proinflammatory cytokines and chemokines via p38-MAPK and NF-kappaB. In the present study, we demonstrate that IL-32 induces differentiation of human blood monocytes as well as THP-1 leukemic cells into macrophage-like cells with functional phagocytic activity for live bacteria. Muramyl dipepide (MDP), the ligand for the intracellular nuclear oligomerization domain (NOD) 2 receptor, has no effect on differentiation alone but augments the monocyte-to-macrophage differentiation by IL-32. Unexpectedly, IL-32 reversed GM-CSF/IL-4-induced dendritic cell differentiation to macrophage-like cells. Whereas the induction of TNFalpha, IL-1beta, and IL-6 by IL-32 is mediated by p38-MAPK, IL-32-induced monocyte-to-macrophage differentiation is mediated through nonapoptotic, caspase-3-dependent mechanisms. Thus, IL-32 not only contributes to host responses through the induction of proinflammatory cytokines but also directly affects specific immunity by differentiating monocytes into macrophage-like cells.
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PMID:Interleukin-32 induces the differentiation of monocytes into macrophage-like cells. 1829 36

Pro-inflammatory cytokines cause beta-cell dysfunction and death. The aim of this study was to investigate the interactions between different pro- and anti-inflammatory cytokines and their effects on apoptotic beta-cell death pathways. Insulin-producing RINm5F cells were exposed to different combinations of cytokines. Gene expression analyses of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) were performed by real-time RT-PCR. Cell viability was measured by the MTT assay, NFkappaB activation using a SEAP reporter gene assay, protein expression by western blotting and caspase-3 activity using the DEVD cleavage method. IL-1beta, tumour necrosis factor alpha (TNFalpha) and a combination of all three pro-inflammatory cytokines increased while IFNgamma alone did not affect NFkappaB activity and iNOS gene and protein expression. Interestingly, the anti-inflammatory cytokines IL-4, IL-13 and IL-10 decreased IL-1beta-stimulated NFkappaB activation and iNOS expression. IL-1beta, TNFalpha and the pro-inflammatory cytokine combination also increased MnSOD gene and protein expression. But IL-4, IL-13 and IL-10 did not affect MnSOD expression and did not modulate IL-1beta-stimulated MnSOD expression. Caspase-3 activity was increased by IL-1beta and the pro-inflammatory cytokine combination, and to a lesser extent by TNFalpha. In contrast, IFNgamma had no effect on caspase-3 activity. IL-4, IL-13 and IL-10 decreased caspase-3 activity and increased viability of insulin-producing cells treated with pro-inflammatory cytokines. The anti-inflammatory cytokines counteracted the cytotoxic effects of pro-inflammatory cytokines in insulin-producing cells. This was achieved through the reduction of nitrosative stress. Thus, a balance between the anti-inflammatory and the pro-inflammatory cytokines is of crucial importance for the prevention of pancreatic beta-cell destruction.
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PMID:Interaction between pro-inflammatory and anti-inflammatory cytokines in insulin-producing cells. 1837 40

Activation of T cells is a critical event in the pathogenesis of concanavalin A (Con A)-induced liver injury, and facilitating apoptosis of activated T cells may provide a strategy for the treatment. Here, we found that the ethanol extract from the stem parts of Dregea volubilis (DVE) inhibited cell proliferation and induced apoptosis, which was selective for Con A-activated, rather than nonactivated, lymph node cells. Administration of DVE prevented mice from Con A-induced elevation of serum transaminases, liver necrosis and increased TNF-alpha, IFN-gamma, IL-2 and IL-4 in mice sera. DVE also caused apoptosis of in vivo activated T cells. In addition, increased active fragments of caspase-3 were found in the DVE-treated cells. But DVE-induced apoptosis was Fas-independent, as it was still observed in T cells from Fas ligand-mutated gld/gld mice. These results suggest that DVE may have great potential to treat T cell-mediated diseases through facilitating apoptosis of activated T cells.
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PMID:Dregea volubilis ameliorates concanavalin A-induced liver injury by facilitating apoptosis of activated T cells. 1853 62


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