The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells.
Compounds suppressing the production of tumor necrosis factor-alpha are protective in animal models of septic shock. Recent studies demonstrated a beneficial effect of xanthine derivatives, which suppress tumor necrosis factor-alpha production by acting as non-specific cAMP phosphodiesterase inhibitors. In this experiment we tested the effect of (+/-)-rolipram (racemate) and its enantiomers on human mononuclear cells stimulated with lipopolysaccharide (LPS). Rolipram has a phenyl-pyrrolidinone structure, unrelated to the methylxanthines, and acts as a specific inhibitor of the type IV phosphodiesterase. Our results identify rolipram as a remarkably potent suppressor of the LPS-induced synthesis of tumor necrosis factor-alpha. When compared to the non-specific inhibitor pentoxifylline, the IC50 of (+/-)-rolipram (130 nM) is more than 500 times lower. The influence of rolipram on tumor necrosis factor-alpha production depended on the steric configuration of the molecule, since the (-)-enantiomer exhibited a five times lower IC50 than the (+)-enantiomer. The inhibitory effect of all substances tested is selective for tumor necrosis factor-alpha rather than interleukin-1 beta, since interleukin-1 beta production is only slightly influenced.
Medizinische Klinik, Klinikum Innenstadt, Universität München, F.R.G.
J
J
Semmler
H
H
Wachtel
S
S
Endres
D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D020889:Rolipram; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D020889:Rolipram