Zazzeroni Francesca, Papa Salvatore, Algeciras-Schimnich Alicia, Alvarez Kellean, Melis Tiziana, Bubici Concetta, Majewski Nathan, Hay Nissim, De Smaele Enrico, Peter Marcus E, Franzoso Guido
Gwen Knapp Center for Lupus and Immunoolgy Research, Ben May Institute, and Committee on Immunology, University of Chicago, IL 60637, USA.
Blood. 2003 Nov 1;102(9):3270-9. doi: 10.1182/blood-2003-03-0689. Epub 2003 Jul 10.
In B lymphocytes, induction of apoptosis or programmed cell death (PCD) by Fas (CD95/APO-1) is suppressed by the triggering of CD40. This suppression controls various aspects of the humoral immune response, including antibody affinity maturation. The opposing effects of these receptors are also crucial to B-cell homeostasis, autoimmune disease, and cancer. Cytoprotection by CD40 involves activation of protective genes mediated by NF-kappa B transcription factors; however, its basis remains poorly understood. Here, we report that, in B cells, Gadd45 beta is induced by CD40 through a mechanism that requires NF-kappa B and that this induction suppresses Fas-mediated killing. Importantly, up-regulation of Gadd45 beta by CD40 precedes Fas-induced caspase activation, as well as up-regulation of other NF-kappa B-controlled inhibitors of apoptosis such as Bcl-xL and c-FLIPL. In the presence of Gadd45 beta, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-xL, Gadd45 beta is unable to hamper the "intrinsic" pathway for apoptosis and in fact appears to block Fas cytotoxicity herein by suppressing a mitochondria-targeting mechanism activated by this receptor. These findings identify Gadd45 beta as a critical mediator of the prosurvival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells.
