ENHANCED TUMOR-NECROSIS-FACTOR SUPPRESSION AND CYCLIC ADENOSINE-MONOPHOSPHATE ACCUMULATION BY COMBINATION OF PHOSPHODIESTERASE INHIBITORS AND PROSTANOIDS

We investigated cooperative effects of phosphodiesterase (PDE) inhibit ors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulat ion and tumor necrosis factor (TNF)-alpha synthesis in human periphera l blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated P BMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids an d PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pe ntoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715 , amrinone and rolipram) to increase cAMP levels in combination with c icaprost was evaluated after 1 h of incubation. The dose-dependent inc rease of cAMP for all PDE inhibitors tested in this combined stimulati on provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC(300)), correlated wit h the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theop hylline excluded from the analysis). Interestingly, by contrast, the s pecific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essent ial mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove thera peutically advantageous. It may occur in inflammatory and infectious d iseases in vivo, since high levels of endogenous prostaglandins are li berated in these conditions.