CD40 engagement prevents peroxisome proliferator-activated receptor gamma agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-kappaB-dependent mechanism.
Peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma and die by apoptosis after PPARgamma agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPARgamma agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPARgamma agonist 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic PPARgamma 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 PPARgamma agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPARgamma agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-kappaB mobilization by 15-deoxy-Delta(12,14)-PGJ(2) and ciglitazone. Interestingly, PPARgamma agonists induced an increase in IkappaBalpha and IkappaBbeta protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-kappaB, as an NF-kappaB inhibitor prevented rescue. Apoptosis induction by PPARgamma ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPARgamma agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.
Ray
Denise M
DM
Department of Environmental Medicine, The Lung Biology and Disease Program, University of Rochester Medical Center, School of Medicine and Dentistry, NY 14642, USA.
Akbiyik
Filiz
F
Bernstein
Steven H
SH
Phipps
Richard P
RP
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology*; D019013:CD40 Antigens / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000494:pharmacology; D045744:Cell Line, Tumor; D020672:I-kappa B Proteins / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists*; D015854:Up-Regulation
D019013:CD40 Antigens; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D047495:PPAR gamma; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand