UNIPROT:P08758 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes results from islet beta-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1beta and gamma-interferon are mediators of this beta-cell cytotoxicity, but the mechanism by which damage occurs is not well understood. In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat beta-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat beta-cell line selected for resistance to cytokine-induced cytotoxicity (833/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832/13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA-mediated suppression of the proapoptotic protein Bax enhances viability of 832/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin- and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both beta-cell lines and primary islets. We conclude that proinflammatory cytokines cause beta-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.
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PMID:Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines. 1664 97

Innate immune cells mediate a first line of defense against pathogens and determine the nature of subsequent acquired immune responses, mainly by producing profound amounts of cytokines. Given these diverse tasks, it is predictable that defective NK and gammadelta(+) T cell responses could be the underlying mechanism for the immunological alterations observed in atopic dermatitis (AD). Indeed, the frequencies of circulating NK cells and gammadelta(+) T cells were profoundly reduced in AD patients. They also displayed a defective ability to sustain TNF-alpha and IFN-gamma, but not IL-4, production after in vitro stimulation, and the defect was restricted to innate immune cells. Surprisingly, on the depletion of CD14(+) monocytes, this selective impairment of TNF-alpha and IFN-gamma production was restored to levels comparable to that observed in controls. Release of IL-10 from monocytes was not a major mechanism of the NK and gammadelta(+) T cell dysfunction. Apoptosis as revealed by annexin V binding, was preferentially observed in NK and gammadelta(+) T cells from AD patients when stimulated in the presence of monocytes, and depletion of monocytes significantly protected these cells from apoptotic cell death. Preferential apoptosis of NK cells by activated monocytes in AD patients was cell-contact-dependent. These results indicate that, once NK and gammadelta(+) T cells in AD patients are in immediate contact with activated monocytes, these cells are specifically targeted for apoptosis, leading to the reduced type 1 cytokine production, thereby directing subsequent acquired immune responses toward a type-2 pattern and increasing susceptibility to infection.
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PMID:NK cells and gamma delta+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis. 1675 21

Marijuana cannabinoids, such as delta-9-tetrahydrocannabinoid (THC), suppress type 1 T-helper 1 (Th1) immunity in a variety of models, including infection with the intracellular pathogen Legionella pneumophila (Lp). To examine the cellular mechanism of this effect, bone marrow-derived dendritic cells (DCs) were purified from BALB/c mice and studied following infection and drug treatment. DCs infected in vitro with Lp were able to protect mice when injected prior to a lethal Lp infection; however, the immunization potential of the Lp-loaded cells along with Th1 cytokine production was attenuated by THC treatment at the time of in vitro infection. In addition, THC-treated and Lp-loaded DCs were poorly stimulated in culture-primed splenic CD4(+) T cells to produce interferon-gamma; however, this stimulating deficiency was reversed by adding recombinant interleukin (IL)-12p40 protein to the cultures. Moreover, THC treatment inhibited the expression of DC maturation markers, such as major histocompatibility complex class II and costimulatory molecules CD86 and CD40 as determined by flow cytometry and suppressed the Notch ligand, Del-ta4, as determined by reverse transcription-polymerase chain reaction. However, THC treatment did not affect other DC functions, such as intracellular killing of Lp, determined by colony-forming unit counts of bacteria, and Lp-induced apoptosis, determined by annexin V staining. In conclusion, the data suggest that THC inhibits Th1 activation by targeting essential DC functions, such as IL-12p40 secretion, maturation, and expression of costimulatory and polarizing molecules.
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PMID:Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. 1683 56

In eukaryotic cells the phospholipid phosphatidylserine (PS) is restricted to the inner plasma-membrane leaflet. This lipid asymmetry, which is maintained by the concerted action of phospholipid transport proteins, is mainly lost during apoptosis. Here, we demonstrate that primary human CD8+ cytotoxic T lymphocytes (CTLs) expose PS on T-cell receptor (TCR)-mediated antigen (Ag) recognition. In contrast to PS externalization on apoptotic cells, activation-induced PS exposure is less pronounced and reversible. Fluorescence microscopic analysis revealed that PS is distributed nonhomogenously over the plasma membrane and concentrated in membrane lipid raft domains at the immunologic synapse. By studying the activity of PS transport proteins using a fluorescence-labeled PS analogue, we found that activation of CTLs inhibited the flippase-mediated inward-directed PS transport without affecting the outward transport. Shielding of exposed PS by annexin V protein during Ag recognition diminished cytokine secretion, activation, and cell-to-cell clustering of Ag-specific CTLs. In summary, our data demonstrate for the first time that externalized PS on Ag-stimulated CTLs is linked to T-cell activation and probably involved in cell-to-cell contact formation at the immunologic synapse.
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PMID:Antigen recognition induces phosphatidylserine exposure on the cell surface of human CD8+ T cells. 1691 27

We have previously shown that the absence of Fas/Fas ligand significantly reduced tissue damage and intestinal epithelial cell (IEC) apoptosis in an in vivo model of T cell-mediated enteropathy. This enteropathy was more severe in IL-10-deficient mice, and this was associated with increased serum levels of IFN-gamma and TNF-alpha and an increase in Fas expression on IECs. In this study, we investigated the potential of IL-10 to directly influence Fas expression and Fas-induced IEC apoptosis. Mouse intestinal epithelial cell lines MODE-K and IEC4.1 were cultured with IFN-gamma, TNF-alpha, or anti-Fas monoclonal antibody (mAb) in the presence or absence of IL-10. Fas expression and apoptosis were determined by FACScan analysis of phycoerythrin-anti-Fas mAb staining and annexin V staining, respectively. Treatment with a combination of IFN-gamma and TNF-alpha induced significant apoptosis. Anti-Fas mAb alone did not induce much apoptosis unless cells were pretreated with IFN-gamma and TNF-alpha. These IECs constitutively expressed low levels of Fas, which significantly increased by preincubation of the cells with IFN-gamma and TNF-alpha. Treatment with cytokine or cytokine plus anti-Fas mAb increased apoptosis, which correlated with a decreased Fas-associated death domain IL-1-converting enzyme-like inhibitory protein (FLIP) level, increased caspase-8 activity, and subsequently increased caspase-3 activity. IL-10 diminished both cytokine- and anti-Fas mAb-induced apoptosis, and this was correlated with decreased cytokine-induced Fas expression, increased FLIP, and decreased caspase-8 and caspase-3 activity. In conclusion, IL-10 modulated cytokine induction of Fas expression on IEC cell lines and regulated IEC susceptibility to TNF-alpha, IFN-gamma, and Fas-mediated apoptosis. These findings suggest that IL-10 directly modulates IEC responses to T cell-mediated apoptotic signals.
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PMID:IL-10 protects mouse intestinal epithelial cells from Fas-induced apoptosis via modulating Fas expression and altering caspase-8 and FLIP expression. 1703 Aug 98

Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8- and 2.6-fold decrease in cell proliferation, respectively) (P<0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8- and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (P<0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 microg ml(-1) VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 microg ml(-1) VP-16 (P<0.001). VP-16 enhanced the release of IL-1beta and TNF-alpha from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (P<0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.
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PMID:Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells. 1704 52

IL-22 is a recently discovered cytokine of the IL-10 family that binds to a class II cytokine receptor composed of IL-22R1 and IL-10R2(c) and influences a variety of immune reactions. As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo. In this study, we report that murine breast cancer cells express functional IL-22R as indicated by RT-PCR studies, immunoblotting, and STAT3 activation assays. Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation. Furthermore, IL-22 induced a cell cycle arrest of EMT6 cells in the G(2)-M phase. IL-22 reduced EMT6 cell numbers and the proliferation rate by approximately 50% as measured by [(3)H]thymidine incorporation. IL-22 treatment of EMT6 tumor-bearing mice lead to a decreased tumor size and a reduced tumor cell proliferation in vivo, as determined by 3'-deoxy-3'-fluorothymidine-positron emission tomography scans. Interestingly, IL-22 did not induce apoptosis, as determined in annexin V binding assay and caspase-3 activation assay and had no effect on angiogenesis in vivo. In conclusion, our results indicate that IL-22 reduced tumor growth by inhibiting signaling pathways such as ERK1/2 and AKT phosphorylation that promote tumor cell proliferation in EMT6 cells. Therefore, IL-22 may play a role in the control of tumor growth and tumor progression.
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PMID:IL-22-mediated tumor growth reduction correlates with inhibition of ERK1/2 and AKT phosphorylation and induction of cell cycle arrest in the G2-M phase. 1711 5

T-cell homeostasis is regulated by several molecules; among these, interleukin (IL)-7 plays an essential role in the survival and homeostatic proliferation of peripheral naive T cells. In a previous study, we investigated whether human mesenchymal stromal cells (MSCs) could be engineered with the IL-7 gene to produce functional level of this cytokine. In the present study, we analyzed the impact of different quantities of IL-7 produced by MSCs on the survival and proliferation of a negative immunoselected naive (CD3(+)/CD45RA(+)) T-cell population. Co-cultivation of peripheral naive T cells with MSCs producing low (16 pg/mL) or high (1000 pg/mL) IL-7 levels or in the presence of exogenous IL-7 (0.01 ng/mL and 100 ng/mL) maintained the CD3(+)/CD45RA(+) naive T-cell phenotype. Chemokine receptor CCR7(+) expression was also maintained among this T-cell population. Naive T-cell molecular characteristics were maintained as assessed by the Vbeta spectratyping complexity score, which showed the maintenance of a broad T-cell repertoire. No Th1 or Th2 differentiation was observed, as assessed by interferon-gamma or IL-4 accumulation. In contrast, only MSCs producing high amounts of IL-7 caused increased activation (CD25 31.2% +/- 12% vs 10% +/- 3.5%; P < .05), proliferation (CD71 17.8+/-7% vs 9.3%+/-3, P < .05), apoptosis (assessed by annexin V: 18.6% +/- 5% vs 14.9% +/- 2.6%; P > .05), and the phase S cell cycle (15% vs 6.9%, P > .05). Exogenous IL-7 exhibited no significant effect. In conclusion, we demonstrated that IL-7 produced by MSCs has a dose-independent effect on naive T-cell survival while exerting a dose-dependent effect on activation/proliferation. Due to the continuous production of IL-7 by engineered cells, our system is more efficacious than exogenous IL-7.
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PMID:Interleukin-7-engineered mesenchymal cells: in vitro effects on naive T-cell population. 1716 6

The outcome of a Plasmodium falciparum infection differs greatly between patients, ranging from an asymptomatic carrier status to the most severe characteristics influenced by activating and inhibiting immune factors. The inhibitory leukocyte immunoglobulin-like receptor (LILRB1/CD85j) plays an important role in the immune response as regulator of cytotoxic T cells and of premature activation and clonal expansion of B cells. To investigate its role in malaria, we analyzed blood samples from malaria patients by cytometric analysis. We found a similar expression pattern of CD85j on PBMC in both patients and healthy children. However, malaria patients presented significantly more CD85j+ CD19+ B cells, which also bound annexin V an indicator of early cell death. We compared the plasma levels of several cytokines, since it was speculated that CD85j expression influences cytokine release. Production of inflammatory cytokines was significantly increased in severe malaria cases. We suggest that in malaria, dying B cells contribute to the overwhelming cytokine release and the impairment of the immune memory.
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PMID:Increase in annexin V-positive B cells expressing LILRB1/ILT2/CD85j in malaria. 1719 37

Polymorphoneutrophils (PMNs) are important effector cells in host defense against pneumonia. However, PMNs can also induce inflammation and tissue damage. To investigate the contribution of PMNs to host defense against pneumococcal pneumonia, we determined the effect of the PMN-depleting rat monoclonal antibody RB6-8C5 (RB6) on survival and inflammatory and cellular response in the lungs to a lethal intranasal infection with a serotype 8 pneumococcus in BALB/c mice. Control mice received rat immunoglobulin G (rIgG). Strikingly, the survival of RB6-treated mice was significantly prolonged compared to that of rIgG-treated mice. Although the numbers of CFU in the lungs were statistically similar in both groups 4, 24, and 32 h after infection, rIgG-treated mice developed higher levels of bacteremia, and histopathological examination of the lungs of infected mice revealed marked differences between RB6- and rIgG-treated mice. RB6-treated mice had focal, perivascular lesions without accompanying parenchymal inflammation, and rIgG-treated mice had diffuse, interstitial parenchymal inflammation. Lung homogenates from the rIgG-treated mice had more leukocytes and significantly more total and apoptotic PMNs as determined by fluorescence-activated cell sorter analysis with Annexin V and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of lung tissue samples. Studies with a pneumolysin-deficient mutant of the serotype 8 strain we used also demonstrated the prolonged survival of RB6- compared to rIgG-treated mice. Taken together, our findings suggest that PMNs enhance the likelihood of early death and alter the pathological response to pneumococcal lung infection in BALB/c mice with serotype 8 pneumonia without significantly affecting bacterial clearance or the cytokine response.
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PMID:Influence of neutropenia on the course of serotype 8 pneumococcal pneumonia in mice. 1729 60

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