PROSTAGLANDIN E(2) INDUCES APOPTOSIS IN RESTING IMMATURE AND MATURE HUMAN-LYMPHOCYTES - A C-MYC-DEPENDENT AND BCL-2-INDEPENDENT ASSOCIATED PATHWAY

Prostaglandin E(2) (PGE(2)) is a known negative regulator of T lymphoc yte proliferation. Previously we have indirectly evidentiated the invo lvement of PGE(2) in apoptosis of lymphocytes both in vitro and in viv o. We have evaluated a possible direct effect of PGE(2) on apoptosis. To this end we have investigated the in vitro effects of PGE(2) on cel l death, and its possible correlation with c-Myc and Bcl-2 proteins. W e used freshly isolated unstimulated human lymphocytes from neonatal t hymus, cord blood and adult peripheral blood. PGE(2) induced DNA fragm entation in both peripheral and cord blood at 10(-7) to 10(-5) M conce ntrations, even though this induction was delayed in peripheral blood with respect to cord blood. Apoptosis induced by PGE(2) was always ass ociated with a dose-dependent increase of cellular steady state c-Myc protein levels, whereas Bcl-2 protein levels were not substantially af fected. Unstimulated thymocytes showed spontaneous DNA fragmentation t hat occurred earlier and at higher levels in PGE(2)- (10(-5) M) treate d cells with respect to untreated controls. Also in these cells, PGE(2 ) produced an early increase of c-Myc protein expression, although Bcl -2 protein levels remained unchanged. In conclusion, PGE(2) induces ap optosis with different kinetics on immature and mature T cells: this i nduction is associated with the increase of c-Myc protein expression a nd seems to be independent from Bcl-2 regulation.