Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells.
Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) 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 PGI2, 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 PGE2. The ID50 for iloprost and cicaprost were 8 nM and 5 nM, respectively, compared to 125 nM for PGE2. Moreover, the prostacyclin analogs as well as PGE2 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-alpha synthesis by cicaprost and PGE2 is probably mediated by an increased intracellular cAMP formation. We were able to show elevated cAMP levels with 1 microM and 10 microM of PGE2 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 syndrome (ARDS) and may offer a therapeutic approach in TNF-alpha mediated pathologic processes.
Eisenhut
T
T
Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-Universität, München, Germany.
Sinha
B
B
Gröttrup-Wolfers
E
E
Semmler
J
J
Siess
W
W
Endres
S
S
D002460:Cell Line; D015232:Dinoprostone / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011465:Prostaglandins, Synthetic; D014409:Tumor Necrosis Factor-alpha; D011464:Epoprostenol; D016285:Iloprost; D015232:Dinoprostone; C043867:cicaprost