The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms

• Published in: The Journal of immunology (1950) 2006-10, Vol.177 (8), p.5068-5076
• Main Authors: Ray, Denise M., Akbiyik, Filiz, Phipps, Richard P.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.177.8.5068

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARγ ligands, including the endogenous ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARγ for apoptosis induction is unknown. In this study, we used a PPARγ dominant-negative approach and a small molecule irreversible PPARγ antagonist and found that these inhibitors prevented PPARγ activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARγ agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARγ but did not kill B lymphocytes, further supporting a non-PPARγ-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARγ may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARγ agonists. Furthermore, these new findings support continued investigation into the use of PPARγ agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.