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J. Biol. Chem., Vol. 277, Issue 49, 46950-46958, December 6, 2002

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CD27 and CD40 Inhibit p53-independent Mitochondrial Pathways in Apoptosis of B Cells Induced by B Cell Receptor Ligation^*

Hidenori Hase, Yumiko Kanno, Hidefumi Kojima, Chikao Morimoto^§, Ko Okumura^¶, and Tetsuji Kobata

From the  Division of Immunology, Institute for Medical Science, Dokkyo University School of Medicine, Tochigi 321-0293, Japan, ^§ Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, and ^¶ Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

B cells in the germinal center are known to undergo apoptosis after B cell receptor (BCR) ligation, a process relevant to immunological tolerance. Human CD27 is a B cell co-stimulatory molecule. The aim of this study was to compare the effects of CD27 and CD40 signals on BCR-mediated apoptosis of B cells. BCR ligation activated mitochondrial apoptotic pathways including down-regulation of Bcl-X_L, dissipation of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-9. Each of these effects was significantly inhibited by CD27 and CD40. Bik expression was weakly but significantly down-regulated by CD27 but up-regulated by CD40. BCR ligation resulted in p53 activation including its phosphorylation at Ser¹⁵, nuclear translocation, and target gene p53AIP1 induction. CD27 and CD40 clearly suppressed these processes. Analyses that used dominant-negative p53 variants revealed a low but still substantial level of BCR-mediated apoptosis and intact mitochondria-mediated apoptotic pathway. These pathways were further inhibited by CD27 and CD40, although the cells showed no p53 phosphorylation or p53AIP1 expression. Our results suggested that, at the mitochondrial level, CD27 and CD40 co-stimulatory signals regulated the p53-amplified apoptotic pathway in B cells through the inhibition of p53-independent apoptotic pathway primarily induced by BCR ligation.

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