Dissociation of oxidant production by peroxisome proliferator-activated receptor ligands from cell death in human cell lines

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Abstract

Ligands of peroxisome proliferator-activated receptors (PPARs) come from a diverse group of chemicals that include pharmaceutical drugs, phthalate plasticizers, steroids, and pesticides. PPAR ligands exhibit a number of effects, including an ability to induce apoptosis in some systems. The mechanism(s) underlying the induction of apoptosis is not known. The current study examined the ability of Wy14643, a fibrate and PPARα agonist, and ciglitazone, a thiazolidinedione and PPARγ agonist, to induce apoptosis as well as the production of oxidants in human Jurkat T cells that express all PPAR isoforms. Treatment with increasing doses of Wy14643 caused a substantial time-dependent increase in the overall oxidant status (as reflected by increased dichlorofluorescein fluorescence) of Jurkat cells without any change in viability except at the highest dose and longest time. Ciglitazone also caused a dose- and time-dependent increase in oxidant production. However, although the extent of this production was less than that seen with Wy14643, ciglitazone caused a dose- and time-dependent increase in apoptosis that could not be inhibited by antioxidants. Confocal micrographs of Jurkat cells loaded with dichlorofluorescein diacetate or dihydrorhodamine 123 and treated with Wy14643 or ciglitazone revealed a punctate pattern of fluorescence at early time points suggestive of a mitochondrial origin for these oxidants. Rotenone and antimycin A prevented Wy14643- but not ciglitazone-induced oxidant production. Other relatively specific PPARγ agonists (15δ-PGJ2, and troglitazone), but not nonspecific agonists (bezafibrate and conjugated linoleic acid), were also able to induce oxidant production in Jurkat cells. These data, as well as the findings that oxidant production could be induced by Wy14643 in A549 cells that lack PPARα, and could not be blocked in Jurkat cells by the PPARα inhibitor MK886, indicate oxidant formation is unrelated to PPARα. These data also suggest that oxidant production induced by PPARα ligands originates in the mitochondria.

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