The biphasic effects of cyclopentenone prostaglandins, prostaglandin J2 and 15-deoxy-Δ12,14-prostaglandin J2 on proliferation and apoptosis in rat basophilic leukemia (RBL-2H3) cells

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-Delta(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 muM PGJ(2) and 15d-PGJ(2) induced cell proliferation, respectively. At high concentrations (10-30 muM) 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 gamma (PPARgamma), since troglitazone, an agonist of PPARgamma 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 muM of the prostaglandins had condensed nuclei, DNA fragmentation and increase in activities of caspase-3 and -9. Moreover, PGJ(2) or 15d-PGJ(2)-jnduced apoptotic effects were prevented by the caspase inhibitor, z-VAD-fink. In conclusion, the PGJ(2) or 15d-PGJ(2)-induced apoptosis in RBL-2H3 cells occurs mainly via mitochondrial pathways instead of by PPARgamma-dependent mechanisms. (C) 2003 Elsevier Inc. All rights reserved.