scholarly journals Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim−/− mice

2011 ◽  
Vol 195 (2) ◽  
pp. 277-291 ◽  
Author(s):  
Toshiyuki Bohgaki ◽  
Julien Mozo ◽  
Leonardo Salmena ◽  
Elzbieta Matysiak-Zablocki ◽  
Miyuki Bohgaki ◽  
...  
Keyword(s):  
T Cells ◽  
Death Receptor ◽  
Death Process ◽  
Caspase 8 ◽  
Intrinsic Apoptotic Pathway ◽  
Immune Disorders ◽  
Loss Of Function ◽  
T Cell Homeostasis ◽  
Apoptotic Pathway ◽  
Cell Death Process

Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim−/− mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8−/− T cells, Bim−/− T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim−/− T cells and restrains autoimmunity in Bim−/− mice.

scholarly journals Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells

2020 ◽  
Vol 117 (23) ◽  
pp. 12961-12968 ◽  
Author(s):  
M. Zeeshan Chaudhry ◽  
Rosaely Casalegno-Garduno ◽  
Katarzyna M. Sitnik ◽  
Bahram Kasmapour ◽  
Ann-Kathrin Pulm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Death Receptor ◽  
Cd8 T Cell ◽  
Cytotoxic T Cell ◽  
Caspase 8 ◽  
Infected Cells

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.

scholarly journals The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

2002 ◽  
Vol 22 (15) ◽  
pp. 5419-5433 ◽  
Author(s):  
Susanne M. A. Lens ◽  
Takao Kataoka ◽  
Karen A. Fortner ◽  
Antoine Tinel ◽  
Isabel Ferrero ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Death Receptor ◽  
Cell Receptor ◽  
Caspase 8 ◽  
Activation Induced Cell Death

ABSTRACT The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4− CD8− T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

scholarly journals Plant Food Anthocyanins Induced Platelet Apoptosis Via BCL-2/BCL-XL Pathway

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4988-4988
Author(s):  
Yang Yan ◽  
Ma Jing ◽  
Tian Jinju ◽  
Chen Liyi ◽  
Songmei Yin ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Plant Food ◽  
Intrinsic Apoptotic Pathway ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Platelet Apoptosis ◽  
Activated Platelets

Abstract Background: Platelets are versatile cells and play important roles in hemostasis/thrombosis, inflammation, and atherosclerosis. The pathogenesis of cardiovascular diseases (CVDs) is linked to platelet hyperactivity which is considered an independent risk factor for CVDs. Platelets are critical for promoting the progression of CVDs, and platelet apoptosis have been reported to be involved in platelet activation. Anthocyanins are major phytochemicals abundant in plant food and have been shown to play a protective role against CVDs. Our previous studies demonstrated that anthocyanins from plant food significantly inhibited platelet activation, adhesion, aggregation and granule secretion, as well as attenuated thrombus growth at both arterial and venous shear stresses in vitro and in vivo, however, the effects of anthocyanin on platelet apoptosis and its mechanisms have not been explored. In the present study, we examined whether anthocyanin Cyanidin-3-glucoside (Cy-3-g) affect platelet apoptosis and the BCL-2/BCL-XL intrinsic apoptotic pathway. Methods: Cy-3-g, the predominant bioactive compound of anthocyanin preparations, was obtained from Polyphenol AS Company in Norway.Purified gel-filtered platelets from healthy volunteers were incubated at 37oC for 40 minutes with different concentrations of Cy-3-g (0.5、5、50μM) or PBS buffer as a control. the activated platelets were triggered with 0.5U thrombin for 15min to induce apoptosis. Mitochondria membrane potential (Δψm) and membrane phospholipid phosphatidylserine (PS) exposure in both activated and resting platelets were assessed by flow cytometry. Cytochrome C release, activation of caspase-3, caspase-8, caspase-9, cleavage of gelsolin, the levels of anti-apoptotic BCL-2 family proteins such as BCL-2, BCL-XL and proapoptotic BCL-2 family proteins Bax, Bak, Bad, Bid and tBid in both activated and resting platelets were measured by western blotting. Results: Cy-3-g at 5μM and 50μM directly induced significant ΔΨm dissipation in activated platelets dose dependently. Correspondingly, 50μM Cy-3-g increased cytochrome C release compared to control. The expression of pro-caspase-8 and pro-caspase-9 decreased, activation of caspase-3, caspase-8 and caspase-9 was induced in activated platelets in both 5μM and 50μM Cy-3-g groups. Both PS exposure and the cleavage of gelsolin increased in activated platelets, however these effects were only observed at Cy-3-g doses as high as 50μM. Cy-3-g did not induce the above changes in resting platelets. The intrinsic apoptotic pathway was initiated by Cy-3-g treatment in activated platelets; Cy-3-g significantly inhibited the expression of BCL-2, BCL-XL and increased the levels of Bax, Bak, Bad and Bid in activated platelets dose dependently. No significant difference was observed in resting platelets. Conclusions: Our data demonstrate for the first time that purified anthocyanin Cy-3-g directly accelerated apoptosis in activated platelets via the BCL-2/BCL-XL pathway. Anthocyanins may possess therapeutic potential for patients suffering from thrombotic conditions. Disclosures No relevant conflicts of interest to declare.

The Role of PNAS-2 in Apoptotic Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4092-4092
Author(s):  
Hai-Rong Wang ◽  
Hua Zhong ◽  
Ji-Hua Zhong ◽  
Fei Xiao ◽  
Jian-Yi Zhu ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Death Receptor ◽  
Multivesicular Body ◽  
Intermembrane Space ◽  
Intrinsic Apoptotic Pathway ◽  
Lysosomal Degradation ◽  
Antibody Microarray ◽  
Apoptotic Pathway ◽  
Endonuclease G ◽  
No Activation

Abstract We recently demonstrated PNAS-2 serving as both an anti-apoptotic gene and an oncogene which is specifically up-regulated in acute leukemic patients (Hai-Rong WANG, et al. Oncology, Accepted). However, its role in apoptotic pathway remains elusive. Antibody microarray was applied to study the apoptosis-associated proteins’ changes to elucidate its role in apoptotic pathway. After PNAS-2 was inhibited by RNA interference, caspase3 was up-regulated confirming that PNAS-2 had an anti-apoptotic function. The activation of extrinsic, receptor-mediated apoptotic pathway was characterized by binding a death ligand to the corresponding death receptor. In this study, there were no changes in TNFα, CD95/Fas, TNFR, FADD, TRADD and caspase8 though Fas ligand decreased, while the apoptotic inhibitors such as DcR1 and FLIP were up-regulated, indicating there was no activation in the extrinsic apoptotic pathway. As to the apoptogenic proteins of classical intrinsic apoptotic pathway, there were no changes in Bax and caspase 9 though Bim was down-regulated, while the apoptotic inhibitors such as Bcl-2, Bcl-XL were up-regulated, indicating there was no activation in the intrinsic apoptotic pathway as well. Apart from the two classical apoptotic pathways (intrinsic and extrinsic), Granzyme B (GraB)-perforin apoptotic pathway is one well defined extrinsic accessory way of triggering apoptosis. In our data, GraB and Perforin were up-regulated, suggesting the GraB-Perforin apoptotic pathway was also activated. The apoptosis-induced factor (AIF) and Cathepsin D (CatD) were also up-regulated. AIF could induce apoptosis via a caspase-independent pathway, and Cat D could selectively escape AIF from mitochondria when translocated into the cytosol from lysosome, while other apoptogenic proteins resided in the intermembrane space of mitochondria such as cytochrome c and endonuclease G remained in the mitochondria (Nicolas Bidere, et al. JBC, 2003). Our data indicated that the AIF-induced-caspase-independent pathway was activated when PNAS-2 was inhibited. The changes in protein levels of CatD, AIF and GraB were confirmed by Western Blot. Mannose-6-Phosphate receptor (M6Pr) is the target receptor for GraB and CatD, mediating uptake of the proteases to form vesicles via endocytosis. This receptor also serves to transport newly synthesized GraB and CatD into the vesicles. The vesicles would form a structure named multivesicular body (MVB), which served to sort vesicles’ content destined for degradation or routing to the lysosome. CHMP5 (the alias of PNAS-2) located in MVB and lysosome, and the loss of CHMP5/PNAS-2 could inhibit lysosomal degradation (Jae-Hyuck Shim, et al. JCB, 2006). As GraB and CatD could trigger apoptosis when they were effluxed from the lysosome, we hypothesize that the overexpression of PNAS-2 in leukemic patients might execute its anti-apoptotic function by increasing the lysosomal degradation of apoptogenic factors in lysosome such as CatD and GraB. Figure Figure

scholarly journals Interferon γ Is Required for Activation-induced Death of T Lymphocytes

2002 ◽  
Vol 196 (7) ◽  
pp. 999-1005 ◽  
Author(s):  
Yosef Refaeli ◽  
Luk Van Parijs ◽  
Stephen I. Alexander ◽  
Abul K. Abbas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Interferon Γ ◽  
Caspase 8 ◽  
Antigen Receptors ◽  
T Cell Homeostasis ◽  
Activation Induced Cell Death ◽  
Ifn Γ

The effector cytokine interferon γ (IFN-γ) may play a role in T cell homeostasis. We have examined the requirement for IFN-γ in one mechanism that regulates T cell expansion and survival, activation-induced cell death (AICD). CD4+ T cells lacking IFN-γ or the Stat1 transcription factor are resistant to AICD. IFN-γ is required for the production of caspases, and retrovirus-mediated expression of caspase-8 restores the sensitivity of Stat1-deficient T cells to AICD. In vitro, IFN-γ limits the expansion of T cells that are stimulated through their antigen receptors. Thus, IFN-γ may function to control the expansion and persistence of T cells by promoting caspase-8–dependent apoptosis.

scholarly journals Redundant role of the cytochrome c-mediated intrinsic apoptotic pathway in pancreatic β-cells

2011 ◽  
Vol 210 (3) ◽  
pp. 285-292 ◽  
Author(s):  
Diana Choi ◽  
Stephanie A Schroer ◽  
Shun Yan Lu ◽  
Erica P Cai ◽  
Zhenyue Hao ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 8 ◽  
Intrinsic Apoptotic Pathway ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Apoptotic Pathway ◽  
Redundant Role

Cytochrome c is one of the central mediators of the mitochondrial or the intrinsic apoptotic pathway. Mice harboring a ‘knock-in’ mutation of cytochrome c, impairing only its apoptotic function, have permitted studies on the essential role of cytochrome c-mediated apoptosis in various tissue homeostasis. To this end, we examined the role of cytochrome c in pancreatic β-cells under homeostatic conditions and in diabetes models, including those induced by streptozotocin (STZ) and c-Myc. Previous studies have shown that both STZ- and c-Myc-induced β-cell apoptosis is mediated through caspase-3 activation; however, the precise mechanism in these modes of cell death was not characterized. The results of our study show that lack of functional cytochrome c does not affect glucose homeostasis or pancreatic β-cell mass under basal conditions. Moreover, the cytochrome c-mediated intrinsic apoptotic pathway is required for neither STZ- nor c-Myc-induced β-cell death. We also observed that the extrinsic apoptotic pathway mediated through caspase-8 was not essential in c-Myc-induced β-cell destruction. These findings suggest that cytochrome c is not required for STZ-induced β-cell apoptosis and, together with the caspase-8-mediated extrinsic pathway, plays a redundant role in c-Myc-induced β-cell apoptosis.

scholarly journals Gene expression profile analysis of gallic acid-induced cell death process

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ho Man Tang ◽  
Peter Chi Keung Cheung
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Gallic Acid ◽  
Time Course ◽  
Early Stage ◽  
Expression Profiles ◽  
Death Process ◽  
Apoptotic Pathway ◽  
Cell Death Pathway ◽  
Cell Death Process

AbstractGallic acid is a natural phenolic compound that displays anti-cancer properties in clinically relevant cell culture and rodent models. To date, the molecular mechanism governing the gallic acid-induced cancer cell death process is largely unclear, thus hindering development of novel therapeutics. Therefore, we performed time-course RNA-sequencing to reveal the gene expression profiles at the early (2nd hour), middle (4th and 6th hour), and late (9th hour) stages of the gallic acid-induced cell death process in HeLa cells. By Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we found significant changes in transcription of the genes in different types of cell death pathways. This involved the ferroptotic cell death pathway at the early stage, apoptotic pathway at the middle stage, and necroptotic pathway at the late stage. Metabolic pathways were identified at all the stages, indicating that this is an active cell death process. Interestingly, the initiation and execution of gallic acid-induced cell death were mediated by multiple biological processes, including iron and amino acid metabolism, and the biosynthesis of glutathione, as targeting on these pathways suppressed cell death. In summary, our work provides a dataset with differentially expressed genes across different stages of cell death process during the gallic acid induction, which is important for further study on the control of this cell death mechanism.

scholarly journals Caspase Activation by Adenovirus E4orf4 Protein Is Cell Line Specific and Is Mediated by the Death Receptor Pathway

2001 ◽  
Vol 75 (2) ◽  
pp. 789-798 ◽  
Author(s):  
Adi Livne ◽  
Ronit Shtrichman ◽  
Tamar Kleinberger
Keyword(s):  
Death Receptor ◽  
Dominant Negative ◽  
Disulfonic Acid ◽  
Ros Generation ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Apoptotic Pathway ◽  
Death Receptor Pathway ◽  
Induced Apoptosis

ABSTRACT Adenovirus E4orf4 protein has been shown to induce transformed cell-specific, protein phosphatase 2A-dependent, and p53-independent apoptosis. It has been further reported that the E4orf4 apoptotic pathway is caspase-independent in CHO cells. Here, we show that E4orf4 induces caspase activation in the human cell lines H1299 and 293T. Caspase activation is required for apoptosis in 293T cells, but not in H1299 cells. Dominant negative mutants of caspase-8 and the death receptor adapter protein FADD/MORT1 inhibit E4orf4-induced apoptosis in 293T cells, suggesting that E4orf4 activates the death receptor pathway. Cytochrome c is released into the cytosol in E4orf4-expressing cells, but caspase-9 is not required for induction of apoptosis. Furthermore, E4orf4 induces accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner, and inhibition of ROS generation by 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis. Thus, our results demonstrate that E4orf4 engages the death receptor pathway to generate at least part of the molecular events required for E4orf4-induced apoptosis.

scholarly journals Necrotic Death Pathway in FAS Receptor Signaling

2000 ◽  
Vol 151 (6) ◽  
pp. 1247-1256 ◽  
Author(s):  
Hirotaka Matsumura ◽  
Yusuke Shimizu ◽  
Yoshiyuki Ohsawa ◽  
Atsuo Kawahara ◽  
Yasuo Uchiyama ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Fas Ligand ◽  
Morphological Changes ◽  
Death Receptor ◽  
Jurkat Cells ◽  
Death Process ◽  
Pyrrolidine Dithiocarbamate ◽  
Death Domain ◽  
Cell Death Process

A caspase 8–deficient subline (JB6) of human Jurkat cells can be killed by the oligomerization of Fas-associated protein with death domain (FADD). This cell death process is not accompanied by caspase activation, but by necrotic morphological changes. Here, we show that the death effector domain of FADD is responsible for the FADD-mediated necrotic pathway. This process was accompanied by a loss of mitochondrial transmembrane potential (ΔΨm), but not by the release of cytochrome c from mitochondria. Pyrrolidine dithiocarbamate, a metal chelator and antioxidant, efficiently inhibited the FADD-induced reduction of ΔΨm and necrotic cell death. When human Jurkat, or its transformants, expressing mouse Fas were treated with Fas ligand or anti–mouse Fas antibodies, the cells died, showing characteristics of apoptosis. A broad caspase inhibitor (z-VAD–fmk) blocked the apoptotic morphological changes and the release of cytochrome c. However, the cells still died, and this cell death process was accompanied by a strong reduction in ΔΨm, as well as necrotic morphological changes. The presence of z-VAD–fmk and pyrrolidine dithiocarbamate together blocked cell death, suggesting that both apoptotic and necrotic pathways can be activated through the Fas death receptor.

Sign in / Sign up

Export Citation Format

Share Document