Possible contribution of prostaglandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononuclear cells

Phosphodiesterase (PDE) 4, mixed PDE3/4, and non-selective PDE inhibitors have been shown to inhibit the proliferation of human peripheral brood mononuclear cells (HPBM). The aim of the present study was to examine whether endogenous prostaglandins, in particular prostaglandin E-2 (PGE(2)), are involved in mediating the antiproliferative actions of PDE inhibitors, by comparing their effects with drugs which elevate or mimic adenosine 3',5'-cyclic monophosphate (cAMP) through mechanisms other than PDE inhibition. Indomethacin significantly reduced the antiproliferative effects of the PDE4 inhibitors rolipram and CDP840 and the mixed PDE3/4 inhibitor zardaverine, increasing the IC50 values from 2.51 mu M to >10 mu M, 0.81 mu M to 2.82 mu M, and 1.58 mu M to 4.82 mu M, respectively (P < 0.05), but did not alter the effects of theophylline. Forskolin, PGE(2), and dibutyryl cAMP also inhibited HPBM proliferation and in the presence of indomethacin the effects of forskolin and dibutyryl cAMP were reduced (although this was not significant), whereas PGE(2) was not affected. Rolipram, CDP840, zardaverine, and dibutyryl cAMP all produced a concentration-related increase in PGE(2) production (P < 0.05, ANOVA), but theophylline significantly increased PGE(2) production only at the highest concentration examined, 1000 mu M. The ability of indomethacin to reduce the antiproliferative effects of rolipram, CDP840, and 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 appears that endogenous PGE(2) is not critical for the antiproliferative actions of theophylline, forskolin, and dibutyryl cAMP in HPBM. These results establish the importance of co-ordinated regulation of the cAMP phosphodiesterase and cyclooxygenase-PGE(2) systems for the regulation of lymphocyte function in man, and have clinical implications for therapeutic approaches to diseases associated with lymphocyte dysregulation. (C) 1999 Elsevier Science Inc.