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CD40 Engagement Prevents Peroxisome Proliferator-Activated Receptor Agonist-Induced Apoptosis of B Lymphocytes and B Lymphoma Cells by an NF-B-Dependent Mechanism¹

Denise M. Ray^*, Filiz Akbiyik^*,, Steven H. Bernstein and Richard P. Phipps^2,*

^* Departments of Environmental Medicine, and Microbiology and Immunology, The Lung Biology and Disease Program, University of Rochester Medical Center, School of Medicine and Dentistry, Lymphoma Biology Program, James P. Wilmot Cancer Center, Rochester, NY 14642; and Department of Biochemistry, Hacettepe University, Ankara, Turkey

Peroxisome proliferator-activated receptor (PPAR) is a transcription factor important in fat metabolism and is emerging as an important regulator of immunity and inflammation. We previously demonstrated that normal and malignant B lineage cells express PPAR and die by apoptosis after PPAR agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPAR agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPAR agonist 15-deoxy-^12,14-PGJ₂ and the synthetic PPAR agonist ciglitazone induced activation of caspase 3 and caspase 9, a decrease in mitochondrial membrane potential, and caused cleavage of the caspase substrate poly(ADP-ribose) polymerase. We next tested whether CD40, whose engagement delivers a potent prosurvival signal for B cells, could protect B cells from PPAR agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPAR agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-B mobilization by 15-deoxy-^12,14-PGJ₂ and ciglitazone. Interestingly, PPAR agonists induced an increase in IB and IB protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-B, as an NF-B inhibitor prevented rescue. Apoptosis induction by PPAR ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPAR agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.

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