The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells

Int J Immunopharmacol. 1993 Apr;15(3):409-13. doi: 10.1016/0192-0561(93)90052-z.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Humans
  • Interleukin-1 / biosynthesis
  • Leukocytes, Mononuclear / metabolism*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pyrrolidinones / pharmacology*
  • Rolipram
  • Stereoisomerism
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Interleukin-1
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • Tumor Necrosis Factor-alpha
  • Rolipram