2 edition of Caspase-8 in T-lymphocytes found in the catalog.
Caspase-8 in T-lymphocytes
Written in English
Caspase-8, an aspartate-specific cysteine protease, is best known for its ability to activate cell death via death receptors such as CD95 (Fas/Apo1). Recent evidence indicates that caspase-8 also has non-apoptotic functions in the transduction of signals via T-cell, B-cell and Toll-like receptors on lymphocytes. Previously, the in vivo role of caspase-8 has eluded analysis in post-natal tissues due to embryonic lethality associated with its deletion in mice. To circumvent embryonic lethality we generated mice with targeted caspase 8 disruption that is restricted to T-lymphocytes (tcasp8 -/-). Caspase-8 ablation protected T-lymphocytes from CD95 ligand but not anti-CD3 induced apoptosis, or apoptosis activated with agents that are known to act through the mitochondria. Importantly, these mice manifested a decrease in the number of peripheral T-cells and impaired activation induced T-cell proliferation (AITP). Caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. Furthermore, mice lacking caspase-8 in T-cells developed a lethal, age dependent lymphoproliferative and lymphoinfiltrative immune disorder. With age, tcasp8 -/- mice developed lymphoadenopathy, splenomegaly and accumulated non-clonal T-cell infiltrates in lung, liver and kidneys accompanied by tissue damage. Casp8-/- T-cells isolated from old mice were in a perpetual state of activation in the absence of any infection or stimulation, which could account for the observed pathological phenotypes. These findings identify an essential, cell stage-specific role for caspase 8 in T-cell homeostasis and T-cell mediated immunity. Also, these studies uncover novel physiological functions for caspase-8 in immune regulation and function.
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R.H. Schwartz, Costimulation of T lymphocytes: the role of CD28, CTLA4, and B7/BB1 in interleukin production and immunotherapy, Cell (). Google Scholar 8. Caspase-8 mediates apoptosis induced by 'death receptors' on the cell's surface. At the same time, it is able to prevent receptor interacting protein kinase (RIPK)-dependent necrosis. Without.
Caspase 8 expression can be induced in various cell types by interferon γ (IFN‐γ) 45, 51, 54 through a mechanism that is likely to be methylation‐independent. 54, 76 In some contexts, IFN‐γ induces caspase 8 through a STAT‐1‐dependent pathway. 53, 54 The predicted STAT‐1 binding sites in the caspase 8 promoter, as discussed above. Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate.
Figure 2: MAbs 1G12 and 3B10 both detect pro-caspase-8 in MEFs from WT mice, but not in MEFs from caspase/-mice. Several smaller bands detected in the caspase/-MEFs, correspond to truncated forms of caspase-8 made in the caspase/-mice since only exons 1 and 2 of mouse caspase-8 were deleted in these knock-out mice and not the region encoding the p18 : Extra bands . Percentages of dead (Live/Dead +) cells, cell positive for caspase 8 and 9 and proliferated CD4 + T lymphocytes following a 4 day-long incubation with EBOV or LPS with or without CLI Mean values ±SE based on triplicates from one of two independent experiments with P values * P.
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Caspase-8 is required for induction of apoptosis through the Fas and TNFR1 receptors. cDNA clone is almost identical to the coding sequence of FLICE or the α1 splice variant of MACH. In the region encoding the antigenic peptide, we found a cytosine (C) at position in cDNA instead of the guanine (G) present in both FLICE and MACHα Cited by: In book: Systemic Sclerosis - An Update on the Aberrant Immune System and Clinical Features caspase 8 binds with its DED.
of activated T lymphocytes but also by the enhanced expression of. Caspase 8 inhibitor z-IETD-fmk, however, failed to rescue the enhanced apoptosis in c-FLIP-deficient T lymphocytes (Figure 3A). We did not detect active form of caspase 8 in either group of T cells (data not shown).Cited by: In addition, it has been shown that IL-2 can prime T cells for death: increased amounts of IL-2 up-regulate FasL and down-regulate FLIPa potent inhibitor of caspase-8 Cited by: T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) using MACS method.
Apoptosis rate was studied at protein level by flow cytometer using Annexin V, and at gene expression level using semi-quantitative RT-PCR method for detection of Fas, FasL, Bcl-2, caspase 8. Caspase-8 plays an important role in death receptor-mediated apoptosis.
In contrast to its apoptotic function, recent studies have suggested caspase-8 also plays a role in the immune response, as. For example, mice with T lymphocyte-specific disruption of caspase-8 display a reduction in mature T lymphocytes and an attenuated immune response to viral infection (Salmena et al., ).
a, Caspase-8 protein showing the death effector domains (DED) and the enzyme subunits (p18 and p11).The location and predicted amino acid substitution of the mutation are indicated by the arrow. The absence of caspase-8 in T lymphocytes alone is sufficient to provoke an age-dependent and lethal immune disorder in mice, a finding that underscores the importance of the multifunctional role of caspase-8 in apoptosis, cell growth, and immune homeostasis.
It is also consistent with studies showing that CD4 − CD8 − CD3 + B + T lymphocytes accumulate in mice with T cell-specific or ubiquitous deficiency of caspase-8 on a Ripk3 null background (Kaiser et al., ; Oberst et al., ).
Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CDinduced apoptosis of peripheral blood lymphocytes (PBLs).
It leads to defects in activation of T-lymphocytes, B. Enzymatic activity of caspase 8 was measured in a fixed amount of 2×10 6 harvested T lymphocytes by fluorometric reaction according to the manufacturer's instructions (Caspase-8 Fluorometric Assay, R&D Systems). Briefly, cells were lysed and a caspase 8-specific peptide, conjugated to a fluorescent reporter molecule, was added.
Caspase-8 processing in primary T cells is detectable by cleavage of its full-length kD form between the procaspase and caspase domains to release a cleaved kD fragment. As shown in Fig. 2 A, no evidence of caspase-8 cleavage was detectable in unstimulated T cells for up to 4 h, or even after overnight culture (data not shown).
Caspase-8 is cleaved in activated lymphocytes, whereas caspase-9 remains as a proenzyme. (A) Caspase-8 is processed in proliferating cells.
PBMCs were stimulated (+) or not (−) with anti-CD3 antibody and IL-2 for 1–4 d, and total proteins from 10 6 cells were analyzed by Western blot using an anti–caspase-8 antiserum. The proenzyme and. Autophagy and apoptosis are two important evolutionarily conserved host defense mechanisms against viral invasion and pathogenesis.
However, the association between the two pathways during the viral infection of T lymphocytes remains to be elucidated. Simian type D retrovirus (SRV) is an etiological agent of fatal simian acquired immunodeficiency syndrome (SAIDS), which can display disease.
Caspase-8, an initiator caspase, is responsible for the activation of downstream executioner caspases that ultimately result in the cell's demise. To examine the function of Caspase-8 in lymphocyte regulation, B cells with a Cre recombinase-mediated deletion of Caspase-8 were studied. Kerkvliet, B.P.
Lawrence, in Comprehensive Toxicology, Cytotoxic T lymphocytes (CTLs) represent one of several types of cells of the immune system that have the capacity to directly kill other cells.
They play a major role in host defense against viral infection, as well as infection by other intracellular pathogens that replicate in the cytoplasm of the host cell.
Traditional role of caspase 8 in extrinsic apoptosis. The great genomics rush of the mid s was a watershed event in the apoptosis field, where new members of the caspases and the Bcl-2 family were discovered on what seemed like a monthly schedule.
D is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase the intracellular ceramide level.
D significantly enhanced FasL-induced caspase activation and apoptosis. D stimulated FasL-induced cell. Cathepsin D activates caspase-8, which is required for subsequent caspase-3 activation.
(A) Immunoblotting. Concentration-dependent cleavage of caspase-8 and -3 proteins by cathepsin D, but not cathepsin B, in cytosolic extracts from freshly isolated human blood neutrophils.
Results are representative of three independent experiments. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. Mandruzzato S, Brasseur F, Andry G, Boon T, van der Bruggen P. J Exp Med. Aug 29;(5) PMID FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b.
Scaffidi C, Medema JP, Krammer PH.As shown in Fig. 3, expression of caspase-8, but not caspase- 3 or caspase-9, made Stat1 −/− T cells sensitive to AICD. Furthermore, upon repeated activation, we detected two bands for caspase-8 by Western blotting, consistent with cleavage of the enzyme as a result of Fas-signaling (data not shown).FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer d.