scholarly journals TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
James A Rickard ◽  
Holly Anderton ◽  
Nima Etemadi ◽  
Ueli Nachbur ◽  
Maurice Darding ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activity ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Inflammatory Phenotype ◽  
Dependent Cell ◽  
Perinatal Lethality ◽  
Induced Apoptosis ◽  
Deficient Mice

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.

scholarly journals Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 630-637 ◽  
Author(s):  
Bing Z. Carter ◽  
Duncan H. Mak ◽  
Wendy D. Schober ◽  
Teresa McQueen ◽  
David Harris ◽  
...  
Keyword(s):  
Cell Death ◽  
Anticancer Agents ◽  
Chinese Herb ◽  
Mitochondrial Pathway ◽  
Leukemic Cells ◽  
Cytochrome C Release ◽  
Knock Out ◽  
Dependent Cell ◽  
Induced Apoptosis

Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (AML) blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1 but not Bcl-2 and Bcl-XL levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8–deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but not the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.

scholarly journals PLEKHO2 inhibits TNFα-induced cell death by suppressing RIPK1 activation

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Chenchen Zhou ◽  
Xueli Zhang ◽  
Cuiping Yang ◽  
Yuan He ◽  
Luo Zhang
Keyword(s):  
Cell Death ◽  
Kinase Inhibitor ◽  
Receptor Interaction ◽  
Ph Domain ◽  
Tnf Α ◽  
Dependent Cell ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

AbstractReceptor interaction protein kinase 1 (RIPK1) plays a diverse role in tumor necrosis factor α (TNFα) signalings. The ubiquitination of RIPK1 is essential for NF-κB activation, whereas its kinase activity promotes apoptosis and necroptosis. However, the mechanisms underlying have not been fully illuminated. Here we report that PH domain-containing family O member 2 (PLEKHO2) inhibits RIPK1-dependent cell death and is necessary for NF-κB activation in response to TNFα. Cells of PLKEHO2 deficiency are more susceptible to TNF-α induced apoptosis and necroptosis with increased RIPK1 activation, which is consistent with the observation that the susceptibility of PLEKHO2−/− cells is effectively prevented by treatment of RIPK1 kinase inhibitor. Moreover, PLEKHO2 deficient cells exhibit compromised RIPK1 ubiquitination and NF-κB activation in response to TNFα. Ultimately, PLEKHO2-deficient mice display greatly increased hepatotoxicity and lethality after TNFα-induced hepatitis. In summary, our study revealed that PLEKHO2 is a novel inhibitor of apoptosis and necroptosis, which plays a key role in regulating RIPK1 ubiquitination and activation

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Eosinophilia in transgenic mice expressing interleukin 5.

1990 ◽  
Vol 172 (5) ◽  
pp. 1425-1431 ◽  
Author(s):  
L A Dent ◽  
M Strath ◽  
A L Mellor ◽  
C J Sanderson
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Lymph Nodes ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Mesenteric Lymph Nodes ◽  
Gene Encoding ◽  
Interleukin 5

Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.

Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1461-1468 ◽  
Author(s):  
Paul G. Ekert ◽  
Anissa M. Jabbour ◽  
Anand Manoharan ◽  
Jacki E. Heraud ◽  
Jai Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Family Members ◽  
Pi3 Kinase ◽  
Minor Role ◽  
Growth And Survival ◽  
Interleukin 3 ◽  
Dependent Cell ◽  
Induced Apoptosis ◽  
A Minor ◽  
Survival Signals

Growth and survival of hematopoietic cells is regulated by growth factors and cytokines, such as interleukin 3 (IL-3). When cytokine is removed, cells dependent on IL-3 kill themselves by a mechanism that is inhibited by overexpression of Bcl-2 and is likely to be mediated by proapoptotic Bcl-2 family members. Bad and Bim are 2 such BH3-only Bcl-2 family members that have been implicated as key initiators in apoptosis following growth factor withdrawal, particularly in IL-3-dependent cells. To test the role of Bad, Bim, and other proapoptotic Bcl-2 family members in IL-3 withdrawal-induced apoptosis, we generated IL-3-dependent cell lines from mice lacking the genes for Bad, Bim, Puma, both Bad and Bim, and both Bax and Bak. Surprisingly, Bad was not required for cell death following IL-3 withdrawal, suggesting changes to phosphorylation of Bad play only a minor role in apoptosis in this system. Deletion of Bim also had no effect, but cells lacking Puma survived and formed colonies when IL-3 was restored. Inhibition of the PI3 kinase pathway promoted apoptosis in the presence or absence of IL-3 and did not require Bad, Bim, or Puma, suggesting IL-3 receptor survival signals and PI3 kinase survival signals are independent.

scholarly journals Peyer's Patch-Deficient Mice Demonstrate That Mycobacterium avium subsp. paratuberculosis Translocates across the Mucosal Barrier via both M Cells and Enterocytes but Has Inefficient Dissemination

2010 ◽  
Vol 78 (8) ◽  
pp. 3570-3577 ◽  
Author(s):  
Luiz E. Bermudez ◽  
Mary Petrofsky ◽  
Sandra Sommer ◽  
Raúl G. Barletta
Keyword(s):  
Mycobacterium Avium ◽  
Intestinal Mucosa ◽  
Peyer's Patches ◽  
Mucosal Barrier ◽  
Peyer’S Patches ◽  
M Cells ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Mycobacterium Avium Subsp Paratuberculosis ◽  
Deficient Mice

ABSTRACT Mycobacterium avium subsp. paratuberculosis, the agent of Johne's disease, infects ruminant hosts by translocation through the intestinal mucosa. A number of studies have suggested that M. avium subsp. paratuberculosis interacts with M cells in the Peyer's patches of the small intestine. The invasion of the intestinal mucosa by M. avium subsp. paratuberculosis and Mycobacterium avium subsp. hominissuis, a pathogen known to interact with intestinal cells, was compared. M. avium subsp. paratuberculosis was capable of invading the mucosa, but it was significantly less efficient at dissemination than M. avium subsp. hominissuis. B-cell knockout (KO) mice, which lack Peyer's patches, were used to demonstrate that M. avium subsp. paratuberculosis enters the intestinal mucosa through enterocytes in the absence of M cells. In addition, the results indicated that M. avium subsp. paratuberculosis had equal abilities to cross the mucosa in both Peyer's patch and non-Peyer's patch segments of normal mice. M. avium subsp. paratuberculosis was also shown to interact with epithelial cells by an α5β1 integrin-independent pathway. Upon translocation, dendritic cells ingest M. avium subsp. paratuberculosis, but this process does not lead to efficient dissemination of the infection. In summary, M. avium subsp. paratuberculosis interacts with the intestinal mucosa by crossing both Peyer's patches and non-Peyer's patch areas but does not translocate or disseminate efficiently.

scholarly journals NK-cell activation is associated with increased HIV transcriptional activity following allogeneic hematopoietic cell transplantation

2018 ◽  
Vol 2 (12) ◽  
pp. 1412-1416
Author(s):  
Louise E. Hogan ◽  
Christian Körner ◽  
Kristen Hobbs ◽  
Camille R. Simoneau ◽  
Cassandra Thanh ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activity ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Killer Cell ◽  
Graft Versus Host ◽  
Key Points ◽  
Hiv 1

Key Points Graft-versus-host effects may lead to HIV-1 reactivation and cell death of infected pre-HCT CD4+ T cells. Natural killer cell activation correlates with in vitro HIV-1 transcriptional activity in the setting of HCT.

scholarly journals A Novel High-Throughput Technique for Identifying Monoclonal Antibodies capable of Death Receptor Induced Apoptosis

2009 ◽  
Vol 2 ◽  
pp. JCD.S3660
Author(s):  
Hang Fai Kwok ◽  
Julie A. Gormley ◽  
Christopher J. Scott ◽  
James A. Johnston ◽  
Shane A. Olwill
Keyword(s):  
Cell Death ◽  
High Throughput ◽  
High Throughput Screening ◽  
False Negative ◽  
Death Receptor ◽  
Annexin V ◽  
Fas Receptor ◽  
Induced Apoptosis

The study of death receptor family induced apoptosis has gained momentum in recent years with the knowledge that therapeutic antibodies targeting DR4 and DR5 (death receptor's 4 and 5) have proved efficacious in multiple clinical trials. The therapeutic rationale is based on targeting and amplifying a tumour tissues normal cell death programme (apoptosis). While advances in the targeting of DR4 and DR5 have been successful the search for an agonistic antibody to another family member, the Fas receptor, has proven more elusive. This is partly due to the differing in vitro and in vivo characteristics of individual antibodies. In order to induce Fas targeted cell death an antibody must be capable of binding to and trimerising the receptor. It has been shown that antibodies capable of performing this function in vivo, with the assistance of tumour associated cells, do not always induce apoptosis in vitro. As a result the use of current methodologies to detect functional antibodies in vitro may have dismissed potential therapeutic candidates ('false negative'). Here we report a novel high throughput screening technique which artificially cross-links antibodies bound to the Fas receptor. By combining this process with Annexin-V and Prodidium Iodide (PI) staining we can select for antibodies which have the potential to induce apoptosis in vivo.

scholarly journals Association of Lactobacillus spp. with Peyer's Patches in Mice

2001 ◽  
Vol 8 (2) ◽  
pp. 320-324 ◽  
Author(s):  
Laura Plant ◽  
Patricia Conway
Keyword(s):  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Adhesion Assay ◽  
Scanning Electron Micrographs ◽  
Intestinal Tissue ◽  
High Adhesion ◽  
Preferential Binding ◽  
Scanning Electron

ABSTRACT Sixteen strains of Lactobacillus isolated from humans, mice, and food products were screened for their capacity to associate with Peyer's patches in mice. In preliminary experiments, in vitro binding to tissue pieces was assessed by scanning electron microscopy, and it was demonstrated qualitatively that 5 of the 16 strains showed some affinity for the Peyer's patches, irrespective of their association with the nonlymphoid intestinal tissue. Lactobacillus fermentum KLD was selected for further study, since, in addition to its intrinsically high adhesion rate, this organism was found to exhibit a preferential binding to the follicle-associated epithelium of the Peyer's patches compared with its level of binding to the mucus-secreting regions of the small intestine. Quantitative assessment of scanning electron micrographs of tissue sections which had been incubated with L. fermentum KLD or a nonbinding control strain, Lactobacillus delbruckii subsp.bulgaricus, supported these observations, since a marked difference in adhesion was noted (P < 0.05). This preferential association of strain KLD with the Peyer's patches was also confirmed with radiolabeled lactobacilli incubated with intestinal tissue in the in vitro adhesion assay. Direct recovery of L. fermentum KLD from washed tissue following oral dosing of mice revealed a distinct association (P < 0.05) between this organism and the Peyer's patch tissue. In contrast, L. delbruckii subsp. bulgaricus showed negligible binding to both tissue types in both in vitro and in vivo adhesion assays. It was concluded that L. fermentum KLD bound preferentially to Peyer's patches of BALB/c mice.

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