Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells

The research described herein evaluates the expression and functional signi ficance of peroxisome proliferator activator receptor-gamma (PPAR-gamma) on B-lineage cells, Normal mouse B cells and a variety of B lymphoma cells re flective of stages of B cell differentiation (e,g,, 70Z/3, CH31, WEHI-231, CH12, and J558) express PPAR-gamma mRNA and, by Western blot analysis, the 67-kDa PPAR-gamma protein. 15-Deoxy-Delta (12,14)-pGJ(2) (15d-PGJ(2)), a PP AR-gamma agonist, has a dose-dependent antiproliferative and cytotoxic effe ct on normal and malignant B cells as shown by [H-3]thymidine and 3-[4,5-di methylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Only PPAR-gamma agonists (thiazolidinediones), and not PPAR-alpha agonists, mimicked the e ffect of 15d-PGJ(2) on B-lineage cells, indicating that the mechanism by wh ich 15d-PGJ(2) negatively affects B-lineage cells involves in part PPAR-gam ma, The mechanism by which PPAR-gamma agonists induce cytotoxicity is via a poptosis, as shown by annexin V staining and as confirmed by DNA fragmentat ion detected using the TUNEL assay, interestingly, addition of PGF(2 alpha) , which was not known to affect lymphocytes, dramatically attenuated the de leterious effects of PFAR-gamma agonists on B lymphomas, Surprisingly, 15d- PGJ(2) induced a massive increase in nuclear mitogen-activated protein kina se activation, and pretreatment with PGF(2 alpha) blunted the mitogen-activ ated protein kinase activation. This is the first study evaluating PPAR-gam ma expression and its significance on B lymphocytes. PFAR-gamma agonists ma y serve as a counterbalance to the stimulating effects of other PGs, namely PGE(2), which promotes B cell differentiation. Finally, the use of PGs, su ch as 15d-PGJ(2), and synthetic PPAR-gamma agonists to induce apoptosis in B-lineage cells may lead to the development of novel therapies for fatal B lymphomas.