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National Institute of Environmental Health Sciences

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Publication Detail

Title: The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms.

Authors: Ray, Denise M; Akbiyik, Filiz; Phipps, Richard P

Published In J Immunol, (2006 Oct 15)

Abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARgamma ligands, including the endogenous ligand 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARgamma for apoptosis induction is unknown. In this study, we used a PPARgamma dominant-negative approach and a small molecule irreversible PPARgamma antagonist and found that these inhibitors prevented PPARgamma activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARgamma agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARgamma but did not kill B lymphocytes, further supporting a non-PPARgamma-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 PPARgamma may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARgamma agonists. Furthermore, these new findings support continued investigation into the use of PPARgamma agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.

PubMed ID: 17015690 Exiting the NIEHS site

MeSH Terms: Apoptosis*; B-Lymphocytes/cytology; B-Lymphocytes/drug effects*; Humans; Ligands; Lymphoma, B-Cell/drug therapy*; Lymphoma, B-Cell/pathology; PPAR gamma*/agonists; PPAR gamma*/antagonists & inhibitors; Prostaglandin D2/analogs & derivatives*; Prostaglandin D2/pharmacology; Reactive Oxygen Species/metabolism; Thiazolidinediones/pharmacology*

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