Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclopentenyl cytosine (CPEC) has been shown to induce apoptosis in human T lymphoblastic cell lines and T cells from leukaemia patients. In this study we have addressed the question of whether CPEC is able to decrease proliferation and effector functions of human alloresponsive T lymphocytes and induce T cell anergy. The proliferative capacity of human peripheral blood mononuclear cells in response to allogeneic stimulation was measured by 5,6-carboxy-succinimidyl-diacetate-fluorescein-ester staining. Flow cytometric analysis was performed using surface CD4, CD8, CD25, CD103 and intracellular perforin, granzyme A, granzyme B, caspase-3 and forkhead box P3 (FoxP3) markers. The in vivo immunosuppressive capacity was tested in a murine skin graft model. Addition of CPEC at a concentration of 20 nM strongly decreased the expansion and cytotoxicity of alloreactive T cells. Specific restimulation in the absence of CPEC showed that the cells became anergic. The drug induced caspase-dependent apoptosis of alloreactive T lymphocytes. Finally, CPEC increased the percentage of CD25(high) FoxP3+ CD4+ and CD103+ CD8+ T cells, and potentiated the effect of rapamycin in increasing the numbers of alloreactive regulatory T cells. Treatment with CPEC of CBA/CA mice transplanted with B10/Br skin grafts significantly prolonged graft survival. We conclude that CPEC inhibits proliferation and cytotoxicity of human alloreactive T cells and induces alloantigen non-responsiveness in vitro.
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PMID:The pyrimidin analogue cyclopentenyl cytosine induces alloantigen-specific non-responsiveness of human T lymphocytes. 1806 97

Carvacrol, an essential oil compound of oregano and thyme, has potential applications as an alternative to antibiotic growth promoters in pig nutrition. Carvacrol is well known for its antibacterial effects, but it is unclear whether there are additional effects on the porcine immune system. In the present study, the influence of carvacrol on porcine blood lymphocytes was examined. The porcine enterocyte cell line IPEC-1 was examined for comparison. Carvacrol inhibited the proliferation of purified lymphocytes with an IC50 of 182+/-67 microM in MTT assays. This was confirmed by CFSE assay. The presence of monocytes in carvacrol-treated lymphocyte preparations had a protective effect on the lymphocytes, significantly raising the IC50 to 516+/-87 microM. FACS analysis of CFSE labelled lymphocyte subsets revealed that gammadelta T cells were less susceptible to carvacrol toxicity than CD4 and CD8 T cells. The reduced lymphocyte proliferation measured after carvacrol exposure was shown to be due to apoptotic cell death, as determined by annexin-V binding and caspase-3 activation. The observed effects were not specific for lymphocytes, since carvacrol similarly induced apoptosis and suppressed proliferation in the porcine enterocyte cell line IPEC-1.
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PMID:Influence of carvacrol on proliferation and survival of porcine lymphocytes and intestinal epithelial cells in vitro. 1826 55

Protein kinase C-theta (PKC-theta) is essential for the activation of T cells in autoimmune disorders, but not in viral infections. To study the role of PKC-theta in bacterial infections, PKC-theta(-/-) and wild-type mice were infected with Listeria monocytogenes (LM). In primary and secondary listeriosis, the numbers of LM-specific CD8 and CD4 T cells were drastically reduced in PKC-theta(-/-) mice, resulting in increased CFUs in spleen and liver of both PKC-theta(-/-) C57BL/6 and BALB/c mice. Furthermore, immunization with peptide-loaded wild-type dendritic cells induced LM-specific CD4 and CD8 T cells in wild-type but not in PKC-theta(-/-) mice. In listeriosis, transfer of wild-type T cells into PKC-theta(-/-) mice resulted in a normal control of Listeria, and, additionally, a selective expression of PKC-theta in LM-specific T cells was sufficient to drive a normal proliferation and survival of these T cells in LM-infected PKC-theta(-/-) recipients, illustrating a cell-autonomous function of PKC-theta in LM-specific T cells. Conversely, adoptively transferred PKC-theta(-/-) T cells were partially rescued from cell death and proliferated in LM-infected wild-type recipients, demonstrating that a PKC-theta deficiency of LM-specific T cells can be partially compensated for by a wild-type environment. Additionally, in vitro experiments showed that only the addition of IL-2, but not an inhibition of caspase-3, induced proliferation and prevented death of PKC-theta(-/-) T cells stimulated with LM-infected wild-type dendritic cells, further demonstrating that the impaired proliferation and survival of PKC-theta(-/-) T cells in listeriosis is not intrinsically fixed and can be experimentally improved.
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PMID:Protein kinase C-theta critically regulates the proliferation and survival of pathogen-specific T cells in murine listeriosis. 1839 Jul 45

Visilizumab, a humanized low-Fc receptor binding anti-CD3 antibody, induces rapid clinical response in patients with steroid-refractory ulcerative colitis (UC). Several effective treatments in IBD have been linked to the induction of mucosal T cell apoptosis. The aim of the present study was to evaluate the effect of visilizumab on the apoptosis of lamina propria (LP) and peripheral blood (PB) lymphocytes isolated from patients with UC. Visilizumab induced dose- and time-dependent apoptosis of LP T cells isolated from non-IBD individuals, UC or CD patients. Maximal effect was seen at a concentration of 100 ng/ml and it was 33% for normal, 34% for UC and 23% for CD LP T cells following 24 h stimulation. Visilizumab induced apoptosis predominantly of CD4(+) LP T cells, whereas CD8(+) LP T cells were relatively resistant to apoptosis. Visilizumab did not induce apoptosis of PB T cells from UC patients. Visilizumab-induced apoptosis of LP T cells was dependent on caspase 3 and 8, but not caspase 9 activation and did not involve the Fas/FasL pathway. Low-Fc receptor binding Abs such as visilizumab may be highly effective for the treatment of UC through induction of apoptosis of LP T cells and rapid elimination of lesional pathogenic T cells in the gut mucosa.
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PMID:Visilizumab induces apoptosis of mucosal T lymphocytes in ulcerative colitis through activation of caspase 3 and 8 dependent pathways. 1842 36

Chemokine CCL21 can effectively attract CCR7(+) dendritic cells (DCs), however its role in this event is poorly understood. In this report, we investigated the effect of exogenous CCL21 expressed in breast cancer MCF-7 on human monocyte-derived DCs. CCL21-transfected MCF-7 stimulation prompted DC functions: migration, antigen-uptake and presentation. The stimulated DCs facilitated Th1 type cytokines production, perforin-forming CD8(+) T cell transformation and final T cell-associated clearance of MCF-7. Moreover, the MCF-7-resourced CCL21 protected DCs from apoptosis significantly, involving up-regulations of Bcl-2 expression and NF-kappaB activity, and reduction of caspase-3. This study provides evidence that tumor-derived CCL21 increases the presentation and apoptosis resistance of DCs, suggesting such a mechanism may be useful for the improvement of tumor cell immunogenicity and anti-tumor response.
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PMID:Tumor transfected with CCL21 enhanced reactivity and apoptosis resistance of human monocyte-derived dendritic cells. 1847 50

The activity of substance P (SP) in the rat thymus seems to be tightly controlled by its bioavailability. In this study, we provide evidence for the expression of the SP-degrading enzyme, neutral endopeptidase (NEP)/CD10, by rat thymocyte subsets, and we illustrate its involvement in the in vivo SP/neurokinin-1 receptor (NK(1)R)-mediated regulation of thymocyte survival and proliferation. NEP/CD10 was expressed at both mRNA and protein levels on a substantial portion (45.5%) of CD5(+) thymocytes, namely on the CD4(+)CD8(+) (double positive; DP) and CD4(+) subsets. Continuous administration of thiorphan, a specific NEP/CD10 inhibitor, by means of miniosmotic pumps, enhanced rat thymocyte preprotachykinin-A (PPT-A) and NK(1)R mRNA expression as well as SP and NK(1)R protein levels in an NK(1)R-dependent manner. Thiorphan increased CD10(+)CD4(+) and CD10(+)DP thymocyte numbers, and an NK(1)R antagonist, (S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)-piperidine-3-yl]ethyl}-4-pheny-1-azoniabicyclo[2.2.2]octane, chloride (SR140333), abrogated these stimulatory effects. In addition, the NEP/CD10 inhibitor stimulated interleukin (IL)-2 production, IL-2 receptor alpha chain expression, and concanavalin A-induced proliferation of CD5(+) thymocytes, and it inhibited spontaneous and NK(1)R-dependent thymocyte apoptosis. The thiorphan-protective antiapoptotic and proliferative effects involved the activation of Akt serine-threonine kinase, subsequent up-regulation of survivin mRNA, down-regulation of procaspase-3 mRNA levels, and suppression of caspase-3 activity, which were inhibited by SR140333 and mimicked by exogenous SP administration. Overall, our findings suggest that by controlling SP availability, NEP/CD10 negatively regulates thymocyte homeostasis and development.
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PMID:Thiorphan-induced survival and proliferation of rat thymocytes by activation of Akt/survivin pathway and inhibition of caspase-3 activity. 1862 88

We have previously demonstrated that multiple immunizations with vector-based vaccines containing transgenes for tumor Ags and a triad of costimulatory molecules (TRICOM) enhance the expansion and functional avidity of Ag-specific memory CD8(+) T cells in a mouse model. However, the effect of enhanced costimulation on human memory CD8(+) T cells is still unclear. The study reported here was an in vitro investigation of the proliferation and function of CEA-specific human memory CD8(+) T cells following enhanced costimulation. Our results demonstrated that TRICOM costimulation enhanced production of multiple cytokines and expansion of CEA-specific memory CD8(+) T cells. The lytic capacity of memory CTLs toward CEA(+) tumors was also significantly enhanced. IL-2R alpha (CD25) was upregulated dramatically following APC-TRICOM stimulation, suggesting that the enhanced expansion of memory CD8(+) T cells may be mediated by increased expression of IL-2R on memory T cells. The enhanced cytokine production and proliferation following TRICOM signaling was completely blocked by the combination of neutralizing Abs against B7-1, ICAM-1, and LFA-3, the costimulatory molecules comprising TRICOM. No difference in T-cell apoptosis was observed between APC-TRICOM and APC-wild-type groups, as determined by annexin V, Bcl-2, and active caspase-3 staining. Results indicated that enhanced costimulation greatly expanded human CEA-specific CD8(+) T cells and enhanced T-cell function, without inducing increased apoptosis of CEA-specific memory CD8(+) T cells.
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PMID:Antigen-presenting cells containing multiple costimulatory molecules promote activation and expansion of human antigen-specific memory CD8+ T cells. 1869 Apr 38

Vascular endothelial-cells injury plays a pivotal role in the pathogenesis of graft-versus-host disease (GVHD) and transplant-associated endothelial injury syndrome. Vascular endothelial cells are an exposed target tissue for immune-mediated injury during GVHD. Early endothelial injury syndromes share common features with acute GVHD. Chronic GVHD leads to a rarefaction of microvessels caused by the infiltration of alloreactive cytotoxic T lymphocytes. In this context, allogeneic reactive cytotoxic T cell may contribute to apoptosis of vascular endothelial cells. The involvement of proteinase-activated receptor (PAR-1) in regulation of apoptosis has been recently recognized in many cell types. We hypothesized that apoptosis of vascular endothelial cells induced by allogeneic cytotoxic T cell are mediated via the PAR-1. Allogeneic CD8(+) T cell, PAR-1 agonist peptide (SFLLRN) induced apoptosis of human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) as assessed by AnnexinV-FITC labeling. To ascertain the mechanism of endothelial apoptosis, we determined that allogeneic CD8(+) T cell, SFLLRN enhanced cleavage of caspase-3 and led to p38MAPK activation as assessed by Western blot. The effects of allogeneic CD8(+) T cell and SFLLRN on apoptosis of vascular endothelial cells were largely prevented by a cleavage-blocking anti-human PAR-1-antibody (ATAP2) and a specific inhibitor of p38MAPK. In concert, these observations provide strong evidence that allogeneic CD8(+) T cell induces apoptosis of human vascular endothelial cells through PAR-1-dependent modulation of intrinsic apoptotic pathway via alterations of p38MAPK and caspase-3.
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PMID:Proteinase-activated receptor-1 mediates allogeneic CD8(+) T cell-induced apoptosis of vascular endothelial cells. 1908 70

Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. While the osteolytic cascade initiated by cytokine release from macrophages has been studied extensively, the involvement of T-lymphocytes in this context is controversial and has been addressed by only a few authors. In a former study we detected that the quantity of T-lymphocytes may be influenced by apoptosis in patients with aseptic loosening. In this study we intended to find out more details about the apoptosis-induced shifting of the T-cell number. We focused our interest on the CD4(+) and CD8(+) T-cells and their relative ratio. Caspase-3 cleaved was evaluated immunohistochemically to detect apoptotic T-cells in capsules and interface membranes from patients with aseptic hip implant loosening and a varying degree of caspase-3 cleaved expression in CD4(+) and CD8(+) T-lymphocytes was detected. Moreover, a relationship between the intensity of the apoptotic reactions and the radiological extent of osteolysis was observed. The number of CD4(+) cells was decreased in the presence of strong apoptotic reactions, respectively extensive osteolysis, while CD8(+) cells were affected to a much lower degree. Thus, the CD4(+)/CD8(+) ratio changed from 1.0 in cases with only small areas of periprosthetic osteolysis and minimally intense apoptosis to 0.33 in cases with large areas of osteolysis. This may suggest a causal relationship between the apoptosis-induced shift in the CD4(+)/CD8(+) ratio and the osteolysis respectively aseptic loosening. It is possible that these findings may lead to a new understanding of particle-induced osteolysis.
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PMID:Association between apoptotis and CD4(+)/CD8(+) T-lymphocyte ratio in aseptic loosening after total hip replacement. 1921 44

We describe the generation of a fusion cytokine consisting of GM-CSF in tandem with N-terminal-truncated MCP-1 (6-76), hereafter GMME1. Treatment of activated T cells with recombinant GMME1 protein leads to proinflammatory cytokine reduction and apoptosis via a CCR2-restricted pathway. Similarly, cell death is triggered in macrophages cultured with GMME1, while an inhibition of Ab production from plasma cells is observed. Treatment of CD4 T cells derived from experimental autoimmune encephalomyelitis mice with GMME1 leads to p38 hyperphosphorylation, inhibition of p44/42, AKT and STAT3 phosphorylation, and caspase-3 activation. GMME1 administration to experimental autoimmune encephalomyelitis mice suppresses symptomatic disease and correlates with decreased levels of inflammatory cytokines including IL-17, MOG-specific Ab titers, and blockade of CD4 and CD8 T cell infiltration in spinal cords. We propose that GMME1 defines a new class of agents for the treatment of autoimmune ailments by selectively targeting lymphomyeloid cells expressing CCR2.
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PMID:Selective inhibition of CCR2 expressing lymphomyeloid cells in experimental autoimmune encephalomyelitis by a GM-CSF-MCP1 fusokine. 1923 56


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