| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
B Activation and Up-Regulation of c-FLIP and Bcl-xL1
* 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;
Département Hématologie-Immunologie et Thérapie Cellulaire and
Service d’Hématologie Clinique, Centre Hospitalo-Universitaire Pontchaillou, Rennes, France;
Institut National de la Santé et de la Recherche Médicale, Unité 866, Université de Bourgogne, Dijon, France; and
¶ Etablissement Français du Sang-Bretagne, Rennes, France
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-xL. The induction of these antiapoptotic molecules as well as the inhibition of TRAIL-induced apoptosis by CD40 is partially abolished when NF-
B 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-B-mediated induction of c-FLIP and Bcl-xL 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-B signaling or a blocking anti-CD40 Ab could be of great interest in FL therapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Région Bretagne, the Association pour le Développement de l’Hémato-Oncologie, and the Université de Rennes 1. M.T. was supported by the Ligue Régionale Contre le Cancer and the Société Francaise d’Hématologie. O.M. is supported by research grants from the Institut National du Cancer (PL098), Agence Nationale de la Recherche (ANR-06-JCJC-0103), and the European community (ApopTrain Marie Curie RTN). A.M. is a recipient of a fellowship from the French Ministry of Research and Education.
2 Address correspondence and reprint requests to Dr. Thierry Guillaudeux, Institut National de la Santé et de la Recherche Médicale, Unité 917 MICA, Faculté de Médecine, Université de Rennes 1, 2, Avenue du Pr Léon Bernard, 35043 Rennes, France. E-mail address: thierry.guillaudeux{at}univ-rennes1.fr
3 Abbreviations used in this paper: FL, follicular lymphoma; GC, germinal center; L, ligand; FLICA, fluorochrome inhibitor of caspases.
This article has been cited by other articles:
|
|
 |
|
  D. Yang, S. Wang, C. Brooks, Z. Dong, P. V. Schoenlein, V. Kumar, X. Ouyang, H. Xiong, G. Lahat, A. Hayes-Jordan, et al. IFN Regulatory Factor 8 Sensitizes Soft Tissue Sarcoma Cells to Death Receptor-Initiated Apoptosis via Repression of FLICE-like Protein Expression Cancer Res., February 1, 2009; 69(3): 1080 - 1088. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
