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

The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor-γ (PPAR-γ) on B-lineage cells. Normal mouse B cells and a variety of B lymphoma cells reflective of stages of B cell differentiation (e.g., 70Z/3, CH31, WEHI-231, CH12, and J558) express PPAR-γ mRNA and, by Western blot analysis, the 67-kDa PPAR-γ protein. 15-Deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ), a PPAR-γ agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [ 3 H]thymidine and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Only PPAR-γ agonists (thiazolidinediones), and not PPAR-α agonists, mimicked the effect of 15d-PGJ 2 on B-lineage cells, indicating that the mechanism by which 15d-PGJ 2 negatively affects B-lineage cells involves in part PPAR-γ. The mechanism by which PPAR-γ agonists induce cytotoxicity is via apoptosis, as shown by annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. Interestingly, addition of PGF 2α , which was not known to affect lymphocytes, dramatically attenuated the deleterious effects of PPAR-γ agonists on B lymphomas. Surprisingly, 15d-PGJ 2 induced a massive increase in nuclear mitogen-activated protein kinase activation, and pretreatment with PGF 2α blunted the mitogen-activated protein kinase activation. This is the first study evaluating PPAR-γ expression and its significance on B lymphocytes. PPAR-γ agonists may serve as a counterbalance to the stimulating effects of other PGs, namely PGE 2 , which promotes B cell differentiation. Finally, the use of PGs, such as 15d-PGJ 2 , and synthetic PPAR-γ agonists to induce apoptosis in B-lineage cells may lead to the development of novel therapies for fatal B lymphomas.