CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL.
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.
Travert
Marion
M
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.
Ame-Thomas
Patricia
P
Pangault
Céline
C
Morizot
Alexandre
A
Micheau
Olivier
O
Semana
Gilbert
G
Lamy
Thierry
T
Fest
Thierry
T
Tarte
Karin
K
Guillaudeux
Thierry
T
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D014066:Palatine Tonsil / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
C416282:BAY 11-7085; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019013:CD40 Antigens; D016328:NF-kappa B; D009570:Nitriles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D013450:Sulfones; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D051020:bcl-X Protein; D023201:CD40 Ligand; D053181:Caspase 8