Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 gamma and die by apoptosis after PPARy agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPARy agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPARy agonist 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic PPAR gamma 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 gamma agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPAR gamma agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-kappa B mobilization by 15-deoxy-Delta(12,14)-PGJ(2) and ciglitazone. Interestingly, PPARy agonists induced an increase in I kappa B alpha and I kappa B beta protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-kappa B, as an NF-kappa B inhibitor prevented rescue. Apoptosis induction by PPAR gamma ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPAR gamma agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.