Possible contribution of prostaglandin E-2 to the antiproliferative effectof phosphodiesterase 4 inhibitors in human mononuclear cells

Phosphodiesterase (PDE) 4, mixed PDE3/4, and non-selective PDE inhibitors h ave been shown to inhibit the proliferation of human peripheral brood monon uclear cells (HPBM). The aim of the present study was to examine whether en dogenous prostaglandins, in particular prostaglandin E-2 (PGE(2)), are invo lved in mediating the antiproliferative actions of PDE inhibitors, by compa ring their effects with drugs which elevate or mimic adenosine 3',5'-cyclic monophosphate (cAMP) through mechanisms other than PDE inhibition. Indomet hacin significantly reduced the antiproliferative effects of the PDE4 inhib itors rolipram and CDP840 and the mixed PDE3/4 inhibitor zardaverine, incre asing the IC50 values from 2.51 mu M to >10 mu M, 0.81 mu M to 2.82 mu M, a nd 1.58 mu M to 4.82 mu M, respectively (P < 0.05), but did not alter the e ffects of theophylline. Forskolin, PGE(2), and dibutyryl cAMP also inhibite d HPBM proliferation and in the presence of indomethacin the effects of for skolin and dibutyryl cAMP were reduced (although this was not significant), whereas PGE(2) was not affected. Rolipram, CDP840, zardaverine, and dibuty ryl cAMP all produced a concentration-related increase in PGE(2) production (P < 0.05, ANOVA), but theophylline significantly increased PGE(2) product ion only at the highest concentration examined, 1000 mu M. The ability of i ndomethacin to reduce the antiproliferative effects of rolipram, CDP840, an d zardaverine, together with the fact that these drugs can stimulate PGE(2) production, suggests that their antiproliferative actions may be mediated in part by stimulation of endogenous PGE(2) production In contrast, it appe ars that endogenous PGE(2) is not critical for the antiproliferative action s of theophylline, forskolin, and dibutyryl cAMP in HPBM. These results est ablish the importance of co-ordinated regulation of the cAMP phosphodiester ase and cyclooxygenase-PGE(2) systems for the regulation of lymphocyte func tion in man, and have clinical implications for therapeutic approaches to d iseases associated with lymphocyte dysregulation. (C) 1999 Elsevier Science Inc.