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1.
David Vermijlen Christopher J. Froelich Dianzhong Luo Nathalie Suarez-Huerta Bernard Robaye Eddie Wisse 《Cancer immunology, immunotherapy : CII》2001,50(4):212-217
Cytotoxic lymphocytes may induce apoptosis in their target cells by the FasL (Fas ligand) pathway or the perforin/granzyme
B pathway. It has been shown that Fas-expressing colon carcinoma (CC) cells are resistant to FasL-mediated apoptosis. The
aims of this study were to determine whether CC cells are also resistant to perforin/granzyme B and whether the FasL resistance
lies upstream of caspase-3 activation. The resistance of the Fas-expressing rat CC531s cells to the FasL pathway was confirmed
by treating them with recombinant human soluble FasL, using rat hepatocytes as a positive control. The intracellular delivery
of granzyme B by sublytic concentrations of perforin, on the other hand, resulted in many features of apoptosis (chromatin
condensation, nucleus fragmentation, loss of microvilli and internucleosomal DNA fragmentation) within 3 h. Since both the
FasL and perforin/granzyme B pathways converge at caspase-3, we measured caspase-3 activity to learn whether the FasL resistance
was due to failure to activate this crucial executioner. Caspase-3 activation occurred in CC531s cells after perforin/granzyme
B treatment, but not after the addition of recombinant FasL. Furthermore, we showed that caspase-3 activity is involved in
the execution of perforin/granzyme-B-induced apoptosis in CC531s cells, since the cell-permeable caspase-3 inhibitor Z-DEVD-FMK
abrogated DNA fragmentation. Together, these results suggest that CC cells are sensitive to perforin/granzyme-B-induced apoptosis
by activating caspase-3 and FasL resistance lies upstream of this executioner caspase.
Received: 20 November 2000 / Accepted: 8 March 2001 相似文献
2.
3.
Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor, is capable of inhibiting synthesis of pro-inflammatory cytokines like IFNγ, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and T helper Type 1 cells. We observed that normal human serum, derived from a healthy individual but containing large amounts of IL-10, inhibited cytotoxic activity and interfered with granzyme B release from alloreactive cytotoxic T cell (CTL) clones in vitro, but did not affect perforin release. The addition of normal human serum containing high levels of anti-IL-10 IgG neutralized the inhibitory effects of IL-10 serum. Moreover, we have identified that cytotoxic activity and granzyme B release from an Epstein-Barr virus (EBV)-specific CTL clone was similarly inhibited in the presence of IL-10 serum, while perforin release was unaffected. Anti-IL-10 IgG serum also appeared to neutralize the inhibitory effect of IL-10 serum on an EBV-specific CTL clone. 相似文献
4.
Induction of apoptosis by cooperative bacteria in the morphogenesis of host epithelial tissues 总被引:9,自引:0,他引:9
Associations with pathogenic bacteria have recently been shown to initiate apoptotic programs in the cells of their animal
hosts, where host cell death is hypothesized to be a response of the immune system, either initiated as a mechanism of host
defense or bacterial offense. In this study, we present evidence that bacterial initiation of apoptosis is neither restricted
to pathogenesis nor to the initation of an immune response. In the cooperative association between the sepiolid squid Euprymna scolopes and the luminous bacterium Vibrio fischeri, the bacteria induce a dramatic morphogenesis of the host tissues during the first few days of interaction between these
partners. The most striking change is the bacteria-triggered loss of an extensive superficial epithelium that potentiates
the infection process. Our analyses of these tissues revealed that the bacteria induce apoptosis in the cells that comprise
this epithelium within hours of the interaction with bacteria. Ultrastructural analysis revealed that after 24 h the integrity
of the epithelium had been lost, i.e., the basement membrane had degenerated and the majority of the cells exhibited signs
of apoptosis, most notably chromatin condensation. Analysis of these tissues with probes that reveal intracellular acidification
showed that the cells first undergo an initial acidification beginning about 6–8 h after exposure to V. fischeri. As determined by end-labeling of DNA fragments, extensive endonuclease activity was detected at approximately 16–20 h post-infection.
These data provide evidence that cooperative bacteria can participate in the remodeling of host tissues through the induction
of host apoptotic programs.
Received: 10 November 1997 / Accepted: 22 April 1998 相似文献
5.
Caruso JA Reiners JJ 《Apoptosis : an international journal on programmed cell death》2006,11(11):1877-1885
BID is an essential component of many apoptotic pathways. Cytosolic proteases cleave BID within an extended loop region, generating
an active truncated fragment which synergizes with BAX and BAK to induce release of apoptogenic factors from mitochondria.
To determine whether other proteins are cleaved in a similar manner as BID, we performed a database search for proteins which
possess sequence similarity with the BID loop region. One of the proteins identified was the Hsc70-interacting protein (HIP).
We analyzed the cleavage pattern of HIP using two known activators of BID: granzyme B and caspase-8. In in vitro cleavage assays using recombinant proteins, human and rat HIP were cleaved by granzyme B. Furthermore, the granzyme B-mediated
cleavage site was mapped to the BID loop-like region of HIP by site-directed mutagenesis. This region was also the target
for caspase-8-mediated cleavage in rat HIP. However, human HIP was not proteolyzed by caspase-8, which probably reflects sequence
differences between human and rat HIP proteins at the P1′ position of the caspase-8 recognition sequence. To determine whether HIP is cleaved during apoptosis, human Jurkat T cells
were exposed to granzyme B and perforin. The results of these studies suggest that granzyme B-mediated loss of HIP expression
occurs in vivo, and in a coordinate fashion with loss of BID, pro-caspase-8 and pro-caspase-3. These data implicate the Hsp70 co-chaperone
HIP in the proteolytic cascade of some apoptotic pathways. 相似文献
6.
Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis 总被引:5,自引:0,他引:5
In this study, we report on novel alterations found in rat intracranial (i.c.) tumor-infiltrating T lymphocytes (TIL) that
are indicative of T cell defects and death. FACS analysis showed that the cytotoxic T cells (CTL) infiltrating rat T9.F gliomas
were CD3ɛ+, αβTCR+, CD8α
+, but CD8β
−. These lymphocytes also stained positive for the B cell-specific marker, CD45RA, as well as Annexin-V, signifying apoptotic
changes. Functional and biochemical analyses were performed to assess whether the aberrant phenotype was linked to other defects.
When CD8α
+ TIL were purified and stimulated in vitro, their proliferative capacity was markedly diminished in comparison with CD3+CD8α
+CD8β
+ T cells isolated from the spleens of naive, non tumor-bearing rats. Furthermore, the mean fluorescence intensity of surface
CD3ɛ was dramatically reduced in the CD3+CD8α
+CD8β
− TIL population as compared with CD3+CD8α
+CD8β
+ TIL from the same tumor-bearing animal. Biochemical studies revealed that the expression of TCRζ and LAT were reduced in
lysates generated from CD8α-purified TIL with respect to CD8α-purified T cells from naive spleen. We believe that these degenerative changes are reflective of chronic T cell receptor
ligation, because in vitro culture of rat splenocytes or purified T cells with ConA or anti-CD3 mAb induced the same alterations.
In vitro, the downregulation of CD8β could be inhibited by the caspase inhibitor, z-VAD. These results suggest that the aberrant CTL phenotype found in the TIL
of glioma-bearing rats may be novel signals for their impending death and degenerating anti-tumor immune function.
Received: 27 February 2001 / Accepted: 26 April 2001 相似文献
7.
Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism
Mieczkowska A Baslé MF Chappard D Mabilleau G 《The Journal of biological chemistry》2012,287(28):23517-23526
Thiazolidinediones (TZDs) represent an interesting treatment of type 2 diabetes mellitus. However, adverse effects such as heart problems and bone fractures have already been reported. Previously, we reported that pioglitazone and rosiglitazone induce osteocyte apoptosis and sclerostin up-regulation; however, the molecular mechanisms leading to such effects are unknown. In this study, we found that TZDs rapidly activated Erk1/2 and p38. These activations were mediated through Ras proteins and GPR40, a receptor expressed on the surface of osteocytes. Activation of this pathway led only to osteocyte apoptosis but not sclerostin up-regulation. On the other hand, TZDs were capable of activating peroxisome proliferator-activated receptor-γ, and activation of this signaling pathway led to sclerostin up-regulation but not osteocyte apoptosis. This study demonstrates two distinct signaling pathways activated in osteocytes in response to TZDs that could participate in the observed increase in fractures in TZD-treated patients. 相似文献
8.
Regulation of apoptosis by protein S-nitrosylation 总被引:1,自引:0,他引:1
Mannick JB 《Amino acids》2007,32(4):523-526
Summary. S-nitrosylation/denitrosylation of critical cysteine residues on proteins serves as a redox switch that regulates the function
of a wide array of proteins. A key signaling pathway that is regulated by S-nitrosylation is apoptotic cell death. Here we
will review the proteins in apoptotic pathways that are known to be S-nitrosylated by endogenous NO production. The targets
and functional consequences of S-nitrosylation during apoptosis are multifaceted, allowing cells to fine tune their response
to apoptotic signals. 相似文献
9.
B chromosome in a rice aneuploid variation 总被引:5,自引:0,他引:5
Z. K. Cheng H. X. Yu H. H. Yan M. H. Gu L. H. Zhu 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2000,101(4):564-568
An awned rice plant was discovered among the progeny of the triploid Zhongxian 3037. Cytological investigation showed that
this awned plant was a variation with extra chromosomes. Based on the properties of the extra chromosomes during both meiosis
and mitosis – e.g., short stature, darkly staining, instability in chromosome number, and lack of synapsis with A chromosomes
– they could be considered to be B chromosomes in rice. The B chromosome(s) in both asexual and sexual progenies exhibited
a unique segregation that is different from that of telotrisomics and other aneuploids. Moreover molecular marker analysis
detected no dosage effects between the B-chromosome plant and the normal diploid of Zhongxian 3037, indicating that the B
chromosomes might not be directly derived from any A-chromosome fragments in rice.
Received: 8 June 1999 / Accepted: 30 December 1999 相似文献
10.
Comparative mapping of QTLs for agronomic traits of rice across environments by using a doubled-haploid population 总被引:11,自引:0,他引:11
Chaofu Lu Lishuuang Shen Ping He Ying Chen Lihuang Zhu Zhenbo Tan Yunbi Xu 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1997,94(1):145-150
We report here the RFLP mapping of quantitative trait loci (QTLs) which affect some important agronomic traits in cultivated
rice. An anther culture-derived doubled-haploid (DH) population was established from a cross between indica and japonica rice
varieties. A molecular linkage map comprising 137 markers was constructed based on this population which covered the rice
genome at intervals of 14.8 cM on average. The linkage map was used to locate QTLs for such important agronomic traits as
heading date, plant height, number of spikelets per panicle, number of grains per panicle, 1 000-grain weight and the percentage
of seed set, by interval mapping. Evidence of genotype-by-environment interaction was found by comparing QTL maps of the same
population grown in three diverse environments. A total of 22 QTLs for six agronomic traits was detected which were significant
in at least one environment, but only seven were significant in all three environments; seven were significant in two environments
and eight could only be detected in a single environment. However, QTLs-by-environment interaction was trait dependent. QTLs
for spikelets and grains per panicle were common across environments while traits like heading date and plant height were
more sensitive to environment.
Received: 22 February 1996 / Accepted: 10 May 1996 相似文献
11.
12.
13.
Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling 总被引:7,自引:0,他引:7
Leskinen MJ Heikkilä HM Speer MY Hakala JK Laine M Kovanen PT Lindstedt KA 《Experimental cell research》2006,312(8):1289-1298
Chymase released from activated mast cells induces apoptosis of vascular smooth muscle cells (SMCs) in vitro by degrading the pericellular matrix component fibronectin, so causing disruption of focal adhesion complexes and Akt dephosphorylation, which are necessary for cell adhesion and survival. However, the molecular mechanisms of chymase-mediated apoptosis downstream of Akt have remained elusive. Here, we show by means of RT-PCR, Western blotting, EMSA, immunocytochemistry and confocal microscopy, that chymase induces SMC apoptosis by disrupting NF-kappaB-mediated survival signaling. Following chymase treatment, the translocation of active NF-kappaB/p65 to the nucleus was partly abolished and the amount of nuclear p65 was reduced. Pretreatment of SMCs with chymase also inhibited LPS- and IL-1beta-induced nuclear translocation of p65. The chymase-induced degradation of p65 was mediated by active caspases. Loss of NF-kappaB-mediated transactivation resulted in downregulation of bcl-2 mRNA and protein expression, leading to mitochondrial swelling and release of cytochrome c. The apoptotic process involved activation of both caspase 9 and caspase 8. The results reveal that, by disrupting the NF-kappaB-mediated survival-signaling pathway, activated chymase-secreting mast cells can mediate apoptosis of cultured arterial SMCs. Since activated mast cells colocalize with apoptotic SMCs in vulnerable areas of human atherosclerotic plaques, they may participate in the weakening and rupture of atherosclerotic plaques. 相似文献
14.
Chemical-induced apoptotic cell death in tomato cells: involvement of caspase-like proteases 总被引:16,自引:0,他引:16
A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian
cells. This chemical-induced cell death was accompanied by the characteristic features of apoptosis in animal cells, such
as typical changes in nuclear morphology, the fragmentation of the nucleus and DNA fragmentation. In search of processes involved
in plant apoptotic cell death, specific enzyme inhibitors were tested for cell-death-inhibiting activity. Our results showed
that proteolysis plays a crucial role in apoptosis in plants. Furthermore, caspase-specific peptide inhibitors were found
to be potent inhibitors of the chemical-induced cell death in tomato cells, indicating that, as in animal systems, caspase-like
proteases are involved in the apoptotic cell death pathway in plants.
Received: 5 August 1999 / Accepted: 14 March 2000 相似文献
15.
Susan F. Vervoordeldonk Astrid Y. Balkenende H. van den Berg A. E. G. Kr. von dem Borne C. E. van der Schoot E. F. Van Leeuwen Ineke C. M. Slaper-Cortenbach C. E. van der Schoot 《Cancer immunology, immunotherapy : CII》1996,42(1):24-30
Our aim is to treat patients with B cell malignancies with radioimmunotherapy using monoclonal antibodies (mAb) such as CD19,
CD20 and CD22. In this study we investigated the rate of internalization and catabolism of these mAb. After 24 h at 37°C,
20% – 25% of initially cell-bound 125I-CD19 mAb and 125I-CD22 mAb was degraded in B cells, whereas almost no degradation occurred after binding of 125I-CD20 mAb. For B cells expressing Fcγ receptor II (FcγRII), isotype-dependent degradation was noted as the CD19 IgG1 mAb
showed an enhanced degradation rate compared to the switch variant IgG2a. The effect of various pharmaceutical agents that
delay the internalization or subsequent degradation of mAb was evaluated. The degradation was inhibited most effectively by
a combination of etoposide and vinblastine, resulting in accumulation of radioactivity in the target cell. Also the simultaneous
application of CD20 or CD22 with 125I-CD19 mAb or of CD20 with 125I-CD22 mAb proved to be a potent inhibitor of the rapid degradation of these mAb, by inhibiting internalization via an FcγRII-mediated
mechanism. Both methods of reducing the degradation of radioiodinated mAb are expected to prolong irradiation of malignant
B cells and consequently result in an enhanced therapeutic effect in vivo.
Received: 22 September 1995 / Accepted: 13 November 1995 相似文献
16.
Kun Li Baitao Wang Lifang Zheng Kun Yang Yuanyuan Li Minmin Hu Dian He 《Bioorganic & medicinal chemistry letters》2018,28(3):273-277
The 1,4-naphthoquinone derivatives bearing 5,7-dimethoxyl moiety were designed, synthesized, and tested as the antitumor agents against five human cancer cell lines (A549, Hela, HepG2, NCI-H460 and HL-60). All the compounds are described herein for the first time. The structure-activity relationships indicated that the presence of chlorine atom at the 2-position was crucial for the antiproliferative activity. Further, the electrochemical properties of the representative compounds (7e, 8e and 9e) were evaluated and a definite correlation between the redox potential and the antiproliferative activity. The most potent compound 9e displayed significant anti-leukemic activity with IC50 value of 3.8?μM in HL-60 cells and weak cytotoxicity with IC50 of 40.7?μM in normal cells WI-38. In mechanistic study for 9e, the increased numbers of apoptotic cells and increased cell population at G2/M phase correlated with ROS generation. Together, our results suggested that the derivatives of 2-chlorine-1,4-naphthoquinone might be the promising candidates for the treatment of promyelocytic leukemia. 相似文献
17.
Helen M. Byrne 《Journal of mathematical biology》1999,39(1):59-89
In this paper we study a mathematical model that describes the growth of an avascular solid tumour. Our analysis concentrates
on the stability of steady, radially-symmetric model solutions with respect to perturbations taken from the class of spherical
harmonics. Using weakly nonlinear analysis, previous results are extended to show how the amplitudes of the asymmetric modes
interact. Attention focuses on a special case for which the model equations simplify. Analysis of the simplified model equations
leads to the identification of a two-parameter family of asymmetric steady solutions, the dimensions of whose stable and unstable
manifolds depend on the system parameters. The asymmetric steady solutions limit the basin of attraction of the radially-symmetric
steady state when it is linearly stable. On the basis of these numerical and analytical results we postulate the existence
of fully nonlinear steady solutions which are stable with respect to time-dependent perturbations.
Received: 25 October 1998 / Revised version: 20 June 1998 相似文献
18.
Ex vivo generation of human anti-melanoma autologous cytolytic T cells by dentritic cell/melanoma cell hybridomas 总被引:3,自引:0,他引:3
Soruri A Fayyazi A Neumann C Schlott T Jung T Matthes C Zwirner J Riggert J Peters JH 《Cancer immunology, immunotherapy : CII》2001,50(6):307-314
Due to their central role in controlling immunity, dendritic cells are logical targets for priming naive cytotoxic T lymphocytes against tumour cells. In a strictly autologous system, we fused dendritic cells with melanoma cells, both of which were derived from patients with metastatic malignant melanoma. Hybridomas were positive for major histocompatibility complex (MHC) class II, CD40, CD54, CD83, CD86, and the pro-inflammatory cytokine interleukin-12. Autologous T lymphocytes were co-incubated with hybridomas. After 6 days, in-vitro-primed T lymphocytes revealed a strong proliferation activity and released Th-1-associated, but not Th-2-associated, cytokines. Furthermore they showed effective anti-melanoma activity, resulting in death of 70 +/- 9% of autologous melanoma cells. After depletion of CD4+ cells from the mixed population of primed T lymphocytes, the remaining CD8+ cells were able to kill 63+/-8% of autologous melanoma cells. Following depletion of CD8+ cells, however, the cytotoxic capacity of the remaining T lymphocytes caused death in only 32+/-6% of autologous melanoma cells. Blocking of MHC class I, but not class II, molecules on hybridomas impaired T cell proliferation, secretion of Th-1-associated cytokines, as well as the cytotoxic activity of primed T cells. These findings strongly suggest that hybridomas deliver melanoma-associated antigens via MHC class I molecules to T lymphocytes, resulting in the generation of CD8+ cytotoxic T lymphocytes with effective anti-melanoma activity in vitro. The data may serve as a basis for the use of hybridomas in the immunotherapy of malignant melanoma in vivo. 相似文献
19.
I. Schubert O. J. L. Oud U. Pich 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1998,96(8):1022-1026
Chromosomes elongated beyond a critical size by balanced rearrangements reduce the viability and fertility of field bean
individuals. The severity of symptoms, ranging from growth retardation to early death of seedlings, increases with the length
of the longest chromosome arm. This is paralleled by the incomplete separation of sister chromatids during nuclear division,
resulting in chromatin connections between daughter nuclei which become disrupted by cell-wall formation and yield chromatid
deletions detectable as micronuclei. By means of the TUNEL assay we show that, compared to the wild-type, a >6-fold higher
number of meristematic cells of karyotypes with chromosome arms surpassing the limit of tolerance reveal apoptotic nuclei
and are prone to die. Thus, terminal chromatid deletions apparently trigger unscheduled apoptosis. Extensive cell death in
meristems is eventually responsible for reduced growth, disturbed development and reduced seed set. Differentiated root tissues
and microspores did not reveal apoptotic nuclei.
Received: 20 November 1997 / Accepted: 9 December 1997 相似文献
20.
C. Renner Gerhard Held Sascha Ohnesorge Stefan Bauer Klaus Gerlach Jan-Peter Pfitzenmeier Michael Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,44(2):70-76
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes,
induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis
contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation,
FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for
perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity
in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative
state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance
of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells
in bi-mAb-mediated apoptosis and necrosis of tumor cells.
Received: 5 December 1996 / Accepted: 16 January 1997 相似文献