PROSTACYCLIN ANALOGS SUPPRESS THE SYNTHESIS OF TUMOR-NECROSIS-FACTOR-ALPHA IN LPS-STIMULATED HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

Recent reports have shown that prostaglandin E(2) (PGE(2)) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE(2) with prostacyclin (PGI(2)) analogs in their potency to influence LPS-stimulated production of interleukin-1 beta (IL-1 beta) and TNF-alpha by human mononuclear cells (MNC). Our results show, that the stable analogs of PGI(2), iloprost and cicaprost, markedly suppress TNF-alpha synthesis in LPS-stimulated MNC without effect on IL-1 beta production. Although there was no significant difference in maximal suppression of TNF-alpha, iloprost and cicaprost reached suppression to 50% of control at 20-fold lower concentrations than PGE(2). The ID50 for iloprost and cicaprost were 8 nM and 5 nM, respectively, compared to 125 nM for PGE(2). Moreover, the prostacyclin analogs as well as PGE(2) suppressed LPS-induced production of TNF-alpha in Mono Mac 6 cells, a permanent human cell line with characteristics of mature monocytes. Suppression of TNF-a synthesis by cicaprost and PGE(2) is probably mediated by an increased intracellular cAMP formation. We were able to show elevated cAMP levels with 1 mu M and 10 mu M of PGE(2) and cicaprost in this system. The suppression of TNF-alpha synthesis may add to the beneficial effects of iloprost reported in animal models of acute respiratory distress syndrom (ARDS) and may offer a therapeutic approach in TNF-alpha mediated pathologic processes.