The biphasic effects of cyclopentenone prostaglandins, prostaglandin J 2 and 15-deoxy-Δ 12,14-prostaglandin J 2 on proliferation and apoptosis in rat basophilic leukemia (RBL-2H3) cells

Abstract

Mast cells produce chemical mediators, including histamine and arachidonate metabolites such as prostaglandin D 2 (PGD 2) after antigen stimulation. Cyclopentenone prostaglandins of the J series, prostaglandin J 2 (PGJ 2) and 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2), are thought to be derivatives of PGD 2. In this study, the biphasic effects of the PGJ 2 and 15d-PGJ 2 on proliferation and apoptosis in rat basophilic leukemia cells (RBL-2H3), a tumor analog of mast cells, were examined. At low concentrations, 1 or 3 μM PGJ 2 and 15d-PGJ 2 induced cell proliferation, respectively. At high concentrations (10–30 μM) both the inhibition of viability and decrease in histamine content in RBL-2H3 cells were dose dependent. These effects were independent of the nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ), since troglitazone, an agonist of PPARγ did not cause any effects in RBL-2H3 cells. Cell death induced by PGJ 2 and 15d-PGJ 2 was the result of apoptotic processes, since RBL-2H3 cells treated with 30 μM of the prostaglandins had condensed nuclei, DNA fragmentation and increase in activities of caspase-3 and -9. Moreover, PGJ 2 or 15d-PGJ 2-induced apoptotic effects were prevented by the caspase inhibitor, z-VAD-fmk. In conclusion, the PGJ 2 or 15d-PGJ 2-induced apoptosis in RBL-2H3 cells occurs mainly via mitochondrial pathways instead of by PPARγ-dependent mechanisms.