Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytohemagglutinin-activated peripheral CD95+ T cells (day 1 T cells) are resistant to CD95-mediated apoptosis. After prolonged interleukin-2 treatment, these T cells become CD95-mediated apoptosis-sensitive (day 6 T cells). To elucidate the molecular mechanism of apoptosis resistance, day 1 and day 6 T cells were tested for formation of the CD95 death-inducing signaling complex (DISC). DISC-associated active Fas-associated DD protein (FADD)-like interleukin-1 beta-converting enzyme-like protease (FLICE) also referred to as MACH/caspase 8 was only found in apoptosis-sensitive day 6 T cells. Further-analysis of mRNA and protein expression levels of apoptosis-signaling molecules FADD, receptor interacting protein, hematopoietic cell protein tyrosine phosphatase, Fas-associated phosphatase-1, FLICE, bel-2, bcl-xL, and, bax-alpha showed that only the expression level of bcl-xL correlated with T cell resistance to CD95-mediated apoptosis (day 1 T cells: bcl-xhiL; day 6 T cells: bcl-XloL). In T cells activated in vitro, up-regulation of bcl-xL, has previously been correlated with general apoptosis resistance. However, the experiments presented suggest that resistance to CD95-mediated apoptosis in T cells can also be regulated at the level of recruitment of FLICE to the DISC.
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PMID:Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex. 917 12

The molecular machinery of apoptosis is evolutionarily conserved with some exceptions. One such example is the Drosophila proapoptotic gene Head involution defective (Hid), whose mammalian homologue is not known. Hid is apoptotic to mammalian cells, and we have examined the mechanism by which Hid induces death. We demonstrate for the first time a role for the extracellular signal-related kinase-1/2 (Erk-1/2) in the regulation of Hid function in mammalian cells. Bcl-2 and an inhibitor of caspase-9 blocked apoptosis, indicative of a role for the mitochondrion in this pathway, and we provide evidence for a role for caspase-8 in Hid-induced apoptosis. Thus, apoptosis was blocked by an inhibitor of caspase-8, deletion of caspase-8 rendered cells resistant to Hid-induced apoptosis, and Hid associated with caspase-8 in cell lysates. The Fas-associated death domain (FADD) was dispensable for the apoptotic function of Hid, indicating that Hid does not require extracellular death receptor signaling for the activation of caspase-8. In activated T cells, the cytokine interleukin-2 blocked caspase-8 processing and apoptosis, suggesting that survival cues from trophic factors may target a Hid-like intermediate present in mammalian cells. Thus, this study shows that Hid engages with conserved components of cellular death machinery and suggests that apoptotic paradigms characterized by FADD-independent activation of caspase-8 may involve a Hid-like molecule in mammalian cells.
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PMID:Head involution defective (Hid)-triggered apoptosis requires caspase-8 but not FADD (Fas-associated death domain) and is regulated by Erk in mammalian cells. 1212 17

The deoxyspergualin derivative LF 15-0195 has demonstrated some efficacy in animal models of autoimmune and graft-versus-host diseases and is currently tested in clinics. The molecular mechanisms of LF 15-0195 immunosuppressive activity remained unknown. We show that exposure to LF 15-0195 sensitizes Jurkat T cells to apoptosis induced by an agonistic anti-CD95 antibody (CH11 clone) and by the cytokine TNF-related apoptosis-inducing ligand. LF 15-0195 does not demonstrate any significant effect on the postmitochondrial activation of caspases, nor does it modify overall expression of CD95, Fas-associated death domain, and procaspase-8. The compound facilitates the recruitment of these molecules to the death-inducing signaling complex (DISC) and enhances caspase-8 and -10 activation, thus increasing cytochrome c and direct IAP binding with low pI (DIABLO)/Smac mitochondrial release. LF 15-0195 also sensitizes Jurkat T cells to CD3-mediated apoptosis, an in vitro model for activation-induced T-cell death (AICD). LF 15-0195-mediated sensitization to AICD was further confirmed in human peripheral T cells exposed to anti-CD3 antibodies, then cultured in the presence of interleukin-2. In these cells, LF 15-0195 increased apoptosis triggered by either anti-CD95 antibodies or CD3 restimulation, whereas no effect was observed on "passive apoptosis." Finally, in bone marrow recipient mice, LF 15-0195 enhanced allogeneic donor T-cell death, which required a functional CD95 pathway. These results suggest that LF 15-0195 sensitizes T cells to AICD by increasing caspase activation at the DISC level in response to CD95 engagement. This original mechanism, together with LF 15-0195 efficacy in various disease models, makes this compound a promising immunosuppressive drug.
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PMID:LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level. 1239 94

Transforming growth factor-beta (TGF-beta), found at the site of most tumors, has been recognized as one of the mechanisms involved in tumor immunological escape. To evaluate its impact on adoptive immunotherapy against cancer, we examined the susceptibility of tumor-specific T cells to TGF-beta in the setting of these T cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific CD4(+) T cells were ex vivo generated by activating with HBV-transfected dendritic cells and selecting with antibodies to CD25 activation molecules, and then expanded with antibodies to CD3/CD28. These T cells expressed higher levels of the type II TGF-beta receptor than nai;ve T cells and exhibited enhanced apoptosis when exposed to TGF-beta. The underlying apoptotic pathway was linked to the dissipation of the mitochondrial inner membrane potential and activation of caspase-9. The absence of caspase-8 activity in TGF-beta-treated T cells suggests that the death receptor system may not be involved in this type of apoptosis. Interleukin-2 (IL-2), which is concomitantly administered with tumor-specific T cells in adoptive immunotherapy, was unable to protect HBV-specific CD4(+) T cells from the pro-apoptotic effect of TGF-beta when added simultaneously with TGF-beta. Interesting, IL-2-pretreated T cells displayed the type II TGF-beta receptor at lower levels and were more resistant to TGF-beta. Together, our findings indicate that the effectiveness of adoptive cancer immunotherapy may be impaired by tumor-derived TGF-beta and appropriate manipulation of exogenous IL-2 might overcome this hurdle.
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PMID:Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T cells prepared for adoptive immunotherapy. 1260 Jul 43

Cellular FLICE inhibitory protein--long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. c-FLIP(L) expression in T cells can also augment activation of the mitogen-activated protein kinase, extracellular signal-related kinase, as well as nuclear factor-kappaB. This contributes to increased production of interleukin-2 and CD25, resulting in hyperproliferation of T cells from c-FLIP(L)-transgenic mice. c-FLIP also heterodimerizes with and activates caspase-8, resulting in increased death of T cells and a selection of a T helper 2 cytokine profile. The effects of c-FLIP on cytolytic function of CD8(+) T cells have not been examined previously. We studied the cytolytic capacity of T cells from c-FLIP(L)-transgenic mice using an antigen-specific system, as well as the consequences during a viral immune response to Coxsackievirus B3 (CVB3). The increased T-cell receptor (TCR) signalling due to c-FLIP did not alter the cytolytic machinery but did reduce cytotoxicity because of decreased surface expression of TCR and CD8. It also produced a Tc2 cytokine profile. These effects of c-FLIP collectively served to diminish the severity of CVB3-induced myocarditis.
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PMID:Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice. 1701 Jan 8

Clonal T-cell expansion in patients with T-large-granular lymphocyte (LGL) leukemia occurs by an undefined mechanism that may be related to Fas apoptosis resistance. Here, we demonstrate polarized expansion of CD8(+) terminal-memory differentiation in such patients, as demonstrated by CD45RA expression and absence of CD62L expression, suggesting repeated stimulation by antigen in vivo. Elimination of antigen-stimulated T cells normally occurs through Fas-mediated apoptosis. We show that cells from LGL leukemia patients express increased levels of c-FLIP and display resistance to Fas-mediated apoptosis and abridged recruitment of proteins that comprise the death-inducing signaling complex (DISC), including the Fas-associated protein with death-domain (FADD) and caspase-8. Exposure to interleukin-2 (IL-2) for only 24 hours sensitized leukemic LGL to Fas-mediated apoptosis with enhanced formation of the DISC, and increased caspase-8 and caspase-3 activities. We observed dysregulation of c-FLIP by IL-2 in leukemic LGL, suggesting a role in Fas resistance. Our results demonstrate that expanded T cells in patients with LGL leukemia display both functional and phenotypic characteristics of prior antigen activation in vivo and display reduced capacity for Fas-mediated DISC formation.
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PMID:Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia. 1799 14

Regulating apoptosis of lymphocytes is an effective strategy for treatment of lymphocyte-mediated diseases. Recently it has been demonstrated that augmenter of liver regeneration (ALR), an enigmatic protein presented ubiquitously in multiple forms among eukaryotes, possesses potent anti-apoptotic activity and supports proliferation of a variety of cells. However, its action on lymphocytes and the underlying mechanism are not completely understood. In this study, we analyzed the effects of recombinant human ALR (rhALR) on apoptosis of human lymphocytes activated with concanavalin A (ConA). Our results showed that rhALR inhibited apoptosis of ConA-activated lymphocytes and revealed reductions in the percentage of apoptotic cells, caspase-3 activation and PARP cleavage in cells treated with rhALR. Furthermore, the BAX/BCL-2 and cytosol/mitochondria cytochrome c ratios were decreased in the intrinsic death pathway and the activation of caspase-8 was also decreased in the extrinsic death pathway in activated lymphocytes treated with rhALR. In addition, rhALR significantly reduced the quantity of interleukin-2. These results demonstrated that rhALR has anti-apoptotic effects on activated lymphocytes through the activation of several apoptosis-related signaling pathways, and shed some light on the effects of rhALR on modulation immune reactions.
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PMID:Augmenter of liver regeneration inhibits apoptosis of activated human peripheral blood lymphocytes in vitro. 2338 27