CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-κB activation and upregulation of c-FLIP and Bcl-XL

Institut National de la Santé et de la Recherche Médicale, Unité 917 MICA, Faculté de Médecine, Université Rennes 1, Institut Fédératif de Recherche 140 Génétique Fonctionnelle Agronomie et Santé, Rennes, France.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(2):1001-11.
Source: PubMed


The TNF family member TRAIL is emerging as a promising cytotoxic molecule for antitumor therapy. However, its mechanism of action and the possible modulation of its effect by the microenvironment in follicular lymphomas (FL) remain unknown. We show here that TRAIL is cytotoxic only against FL B cells and not against normal B cells, and that DR4 is the main receptor involved in the initiation of the apoptotic cascade. However, the engagement of CD40 by its ligand, mainly expressed on a specific germinal center CD4(+) T cell subpopulation, counteracts TRAIL-induced apoptosis in FL B cells. CD40 induces a rapid RNA and protein up-regulation of c-FLIP and Bcl-x(L). The induction of these antiapoptotic molecules as well as the inhibition of TRAIL-induced apoptosis by CD40 is partially abolished when NF-kappaB activity is inhibited by a selective inhibitor, BAY 117085. Thus, the antiapoptotic signaling of CD40, which interferes with TRAIL-induced apoptosis in FL B cells, involves NF-kappaB-mediated induction of c-FLIP and Bcl-x(L) which can respectively interfere with caspase 8 activation or mitochondrial-mediated apoptosis. These findings suggest that a cotreatment with TRAIL and an inhibitor of NF-kappaB signaling or a blocking anti-CD40 Ab could be of great interest in FL therapy.

Download full-text


Available from: Marion Travert,
  • Source
    • "Studies implicating NFκB in TRAIL induced apoptosis are few in number and conflicting. NFκB expression is shown to be involved in protection against TRAIL (Travert et al. 2008), but a functional NFκB binding site is located in the promoter region of DR4 (Mendoza et al. 2008). NFκB has been reported to enhance TRAIL induced apoptosis through intronic regulation of DR5 (Chen et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Decoy receptors bind with TNF related apoptosis inducing ligands (TRAIL) but do not contain the cytoplasmic domains necessary to transduce apoptotic signals. We hypothesized that decoy receptors may confer neuronal protection against lethal ischemia after ischemic preconditioning (IPC). MAIN METHOD: Mixed cortical neurons were exposed to IPC one day prior to TRAIL treatment or lethal ischemia. IPC increased decoy receptor but reduced death receptor expression compared to lethal ischemia. IPC-induced increase in decoy receptor expression was reduced by prior treatment with CAPE, a nuclear factor-kappa B inhibitor (NFκB). Expression of decoy molecules, dependent on NFκB, may mediate neuronal survival induced by IPC.
    Life sciences 02/2011; 88(15-16):670-4. DOI:10.1016/j.lfs.2011.02.004 · 2.70 Impact Factor
  • Source
    • "The level of cFLAR protein determined by Western blot follows the same trend (Fig. 6a). The increased anti-apoptotic responses to the toxigenic strain challenge correlate with the induction of higher transcription of Nf-κB1 (Table 1), a gene which may have some anti-apoptotic effects[31,32]. In addition the Nf-κB inhibitor QNZ reduces cFLAR expression (Fig. 6b) in agreement with its higher level in the toxigenic strain infection (Fig. 6a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bacillus anthracis secretes several virulence factors targeting different host organs and cell types during inhalational anthrax infection. The bacterial expression of a key virulence factor, lethal toxin (LeTx) is closely tied to another factor, edema toxin (EdTx). Both are transcribed on the same virulence plasmid (pXO1) and both have been the subject of much individual study. Their combined effect during virulent anthrax likely modulates both the global transcriptional and the phenotypic response of macrophages and phagocytes. In fact, responses brought about by the toxins may be different than each of their individual effects. Here we report the transcriptional and apoptotic responses of the macrophage-like phagocytic cell line THP-1 exposed to B. anthracis Sterne (pXO1+) spores, and B. anthracis Delta Sterne (pXO1-) spores. These cells are resistant to LeTx-induced cytolysis, a phenotype seen in macrophages from several mouse strains which are sensitive to toxigenic anthrax infection. Our results indicate that the pXO1-containing strain induces higher pro-inflammatory transcriptional responses during the first 4 hours of interaction with bacterium, evident in the upregulation of several genes relevant to Nf-kappaB, phosphatases, prostaglandins, and TNF-alpha, along with decreases in expression levels of genes for mitochondrial components. Both bacterial strains induce apoptosis, but in the toxigenic strain-challenged cells, apoptosis is delayed. This delay in apoptosis occurs despite the much higher level of TNF-alpha secretion induced by the toxigenic-strain challenge. Interestingly, CFLAR, an important apoptotic inhibitor which blocks apoptosis induced by large amounts of extracellular TNF-alpha, is upregulated significantly during toxigenic-strain infection, but not at all during non-toxigenic-strain infection, indicating that it may play a role in blocking or delaying TNF-alpha-mediated apoptosis. The suppression of apoptosis by the toxigenic anthrax strain is consistent with the notion that apoptosis itself may represent a protective host cell response.
    BMC Immunology 12/2008; 9(1):67. DOI:10.1186/1471-2172-9-67 · 2.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TRAIL is involved in immune tumor surveillance and is considered a promising anti-cancer agent owing to its limited side effects on healthy cells. However, some cancer cells display resistance, or become resistant to TRAIL-induced cell death. Hyperthermia can enhance sensitivity to TRAIL-induced cell death in various resistant cancer cell lines, including lung, breast, colon or prostate carcinomas. Mild heat shock treatment has been proposed to restore Fas ligand or TRAIL-induced apoptosis through c-FLIP degradation or the mitochondrial pathway. We demonstrate here that neither the mitochondria nor c-FLIP degradation are required for TRAIL-induced cell death restoration during hyperthermia. Our data provide evidence that insolubilization of c-FLIP, alone, is sufficient to enhance apoptosis induced by death receptors. Hyperthermia induced c-FLIP depletion from the cytosolic fraction, without apparent degradation, thereby preventing c-FLIP recruitment to the TRAIL DISC and allowing efficient caspase-8 cleavage and apoptosis. Hyperthermia-induced c-FLIP depletion was independent of c-FLIP DED2 FL chain assembly motif or ubiquitination-mediated c-FLIP degradation, as assessed using c-FLIP point mutants on lysine 167 and 195 or threonine 166, a phosphorylation site known to regulate ubiquitination of c-FLIP. Rather, c-FLIP depletion was associated with aggregation, because addition of glycerol not only prevented the loss of c-FLIP from the cytosol but also enabled c-FLIP recruitment within the TRAIL DISC, thus inhibiting TRAIL-induced apoptosis during hyperthermia. Altogether our results demonstrate that c-FLIP is a thermosensitive protein whose targeting by hyperthermia allows restoration of apoptosis induced by TNF ligands, including TRAIL. Our findings suggest that combining TRAIL agonists with whole-body or localized hyperthermia may be an interesting approach in cancer therapy.
    Cell Death & Disease 02/2015; 6(2):e1633. DOI:10.1038/cddis.2015.12 · 5.01 Impact Factor
Show more