The Endoplasmic Reticulum Is a Key Component of the Plasma Cell Death Pathway

Pelletier, Nadège; Casamayor-Pallejà, Montserrat; Luca, Karelle De; Mondière, Paul; Saltel, Frédéric; Jurdic, Pierre; Bella, Chantal; Genestier, Laurent; Defrance, Thierry

doi:10.4049/jimmunol.176.3.1340

Cited by 55 publications

(59 citation statements)

References 32 publications

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“…The loss of naive B cell-derived PCs correlates with loss of IgM secretion over time. Adaptation to secretory load is essential for PC differentiation, and secretory stress contributes to cell death in ASCs (12)(13)(14)46). In the context of such a model, secretion of IgM may drive greater stress (14), because of the more stringent requirements for assembly of pentameric complexes (52).…”

Section: Discussionmentioning

confidence: 99%

“…However, direct evidence for the extended longevity of human PCs is currently lacking (1). A short ASC life span is directly related to the stress of Ab secretion (12)(13)(14), whereas the number of PCs maintained in the long-lived pool is constrained by the availability of niches providing survival signals (1,2,4). Longevity of established PCs may be restricted by competition for niche space, and in this competitive model, PC intrinsic features contribute to determine life span by controlling migration, homing, and niche affinity (1,6,7).…”

Section: P Lasma Cells (Pcs) Critical Effectors Of Humoral Immunity mentioning

confidence: 99%

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In Vitro Generation of Long-lived Human Plasma Cells

Cocco

Stephenson

Care

et al. 2012

The Journal of Immunology

102

152

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Plasma cells (PCs), the terminal effectors of humoral immunity, are short-lived unless supported by niche environments in which they may persist for years. No model system has linked B cell activation with niche function to allow the in vitro generation of long-lived PCs. Thus, the full trajectory of B cell terminal differentiation has yet to be investigated in vitro. In this article, we describe a robust model for the generation of polyclonal long-lived human PCs from peripheral blood B cells. After a proliferative plasmablast phase, PCs persist in the absence of cell division, with viability limited only by elective culture termination. Conservative predictions for PC life expectancy are 300 d, but with the potential for significantly longer life spans for some cells. These long-lived PCs are preferentially derived from memory B cells, and acquire a CD138high phenotype analogous to that of human bone marrow PCs. Analysis of gene expression across the system defines clusters of genes with related dynamics and linked functional characteristics. Importantly, genes in these differentiation clusters demonstrate a similar overall pattern of expression for in vitro and ex vivo PCs. In vitro PCs are fully reprogrammed to a secretory state and are adapted to their secretory load, maintaining IgG secretion of 120 pg/cell/day in the absence of XBP1 mRNA splicing. By establishing a set of conditions sufficient to allow the development and persistence of mature human PCs in vitro, to our knowledge, we provide the first platform with which to sequentially explore and manipulate each stage of human PC differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: P Lasma Cells (Pcs) Critical Effectors Of Humoral Immunity mentioning

confidence: 99%

In Vitro Generation of Long-lived Human Plasma Cells

Cocco

Stephenson

Care

et al. 2012

The Journal of Immunology

102

152

View full text Add to dashboard Cite

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“…75). Yet caspase-4 also resembles caspase-12 in its ability to contribute to apoptosis induced by ER-mediated stress (31,32), though this remains controversial (33). It seems, therefore, that human caspase-4 and caspase-5 have acquired additional diverse functions during their evolution.…”

Section: Discussionmentioning

confidence: 99%

“…Following its initial cloning (28 -30), caspase-4 was without an assigned function until recently, when it was shown to have a role in endoplasmic reticulum (ER) 3 stress-mediated apoptosis (31,32), though this has been disputed (33). Phylogenetic classification (34) places human caspase-4 in a group along with caspases 1, 5, 11, and 12, found only in vertebrates, and named the inflammatory caspases based on the prototype of this group caspase-1.…”

mentioning

confidence: 99%

Caspase-4 Interacts with TNF Receptor-Associated Factor 6 and Mediates Lipopolysaccharide-Induced NF-κB-Dependent Production of IL-8 and CC Chemokine Ligand 4 (Macrophage-Inflammatory Protein-1β)

Lakshmanan

Porter

2007

The Journal of Immunology

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Human caspase-4 does not have a corresponding mouse ortholog. Caspase-4 falls within the class of “inflammatory caspases,” being homologous with human caspases 1 and 5 and mouse caspases 1, 11, and 12. To address the function of caspase-4, we generated caspase-4-deficient human THP1 monocytic cell lines which exhibited substantially reduced LPS-induced secretion of several chemokines and cytokines, including IL-8 (CXCL8), CCL4 (macrophage-inflammatory protein-1β), CCL20 (macrophage-inflammatory protein-3α), and IL-1β. The LPS-induced expression of the mRNAs encoding these cytokines was correspondingly reduced in the caspase-4-deficient clones. Because a specific NF-κB inhibitor blocked LPS-induced IL-8 and CCL4 mRNA expression as well as IL-8 and CCL4 secretion in THP1 cells, we investigated the role of caspase-4 in NF-κB signaling. LPS-induced NF-κB nuclear translocation and activation were inhibited in all caspase-4-deficient clones. LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4. Mutation of this site in caspase-4 resulted in the loss of the TRAF6-caspase-4 interaction. Similar TRAF6-binding motifs are known to be functionally important for TRAF6 interactions with other molecules including caspase-8, and for mediating NF-κB activation in various immune and nonimmune cell types. Our data suggest that the TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-κB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells.

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“…Expression of caspases-4 was significantly up regulated at all concentrations, which is believed to initiate apoptosis through the endoplasmic reticulum death pathway. [31] The expression of the anti-apoptotic factor, Bcl-2, which also plays an important role in the mitochondria-mediated apoptosis,[32] was effectively suppressed at 120 μg/mL and Bcl-2 suppression are thought to be involved in S and G2/M cell cycle phases arrest. [3334]…”

Section: Discussionmentioning

confidence: 99%

Crude ethyl acetate extract of marine microalga,Chaetoceros calcitrans, induces Apoptosis in MDA-MB-231 breast cancer cells

et al. 2014

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Background:Marine brown diatom Chaetoceros calcitrans and green microalga Nannochloropsis oculata are beneficial materials for various applications in the food, nutraceutical, pharmaceutical and cosmeceutical industries.Objective:This study investigated cytotoxicity of different crude solvent extracts from C. calcitrans and N. oculata against various cancer cell lines.Materials and Methods:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was carried out to screen the cytotoxic effects of hexane (Hex), dichloromethane (DCM), ethyl acetate, and methanol extract from C. calcitrans and N. oculata toward various cancer cell lines. Flow cytometry cell cycle was used to determine the cell cycle arrest while the mode of cell death was investigated through acridine orange/propidium iodide (AOPI) staining, Annexin V-Fluorescein Isothiocyanate (FITC) and Terminal deoxynucleotidyl transferase-mediated d-UTP Nick End Labeling (TUNEL) assays. Expression profile of apoptotic and proliferative-related genes was then determined using the multiplex gene expression profiler (GeXP).Results:Crude ethyl acetate (CEA) extract of C. calcitrans inhibited growth of MDA-MB-231 cells, with IC50 of 60 μg/mL after 72 h of treatment. Further studies were conducted to determine the mode of cell death at various concentrations of this extract: 30, 60 and 120 μg/mL. The mode of cell death was mainly apoptosis as shown through apoptosis determination test. The expression data from GeXP showed that caspase-4 was upregulated while B-cell leukemia/lymphoma 2(Bcl-2) was down regulated. Thus, caspase-4 induction endoplasmic reticulum death pathway is believed to be one of the mechanisms underlying the induction of apoptosis while Bcl-2 induced S and G2/M cell cycle phase arrest in MDA-MB-231 cells.Conclusion:CEA extract of C. calcitrans showed the highest cytotoxicity on MDA-MB-231 via apoptosis.

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The Endoplasmic Reticulum Is a Key Component of the Plasma Cell Death Pathway

Cited by 55 publications

References 32 publications

In Vitro Generation of Long-lived Human Plasma Cells

In Vitro Generation of Long-lived Human Plasma Cells

Caspase-4 Interacts with TNF Receptor-Associated Factor 6 and Mediates Lipopolysaccharide-Induced NF-κB-Dependent Production of IL-8 and CC Chemokine Ligand 4 (Macrophage-Inflammatory Protein-1β)

Crude ethyl acetate extract of marine microalga,Chaetoceros calcitrans, induces Apoptosis in MDA-MB-231 breast cancer cells

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