THE SPECIFIC TYPE-IV PHOSPHODIESTERASE INHIBITOR ROLIPRAM DIFFERENTIALLY REGULATES THE PROINFLAMMATORY MEDIATORS TNF-ALPHA AND NITRIC-OXIDE

We compared the effect of the specific type IV phosphodiesterase inhibitor rolipram on intracellular cAMP concentration, nitric oxide (NO) and tumour necrosis factor-alpha(TNF) formation in the murine macrophage cell line RAW 264.7. We found a dose-dependent increase of nitrite accumulation in LPS-stimulated macrophages from 17.5 to 25.1 mu M nitrite with rolipram, whereas TNF synthesis was suppressed to less than 30% of control. This was accompanied by an increase from 7.4 to a maximum of 10.5 nM cAMP in RAW cells incubated with rolipram. These results were confirmed with the stable cAMP analogue (S)-p-adenosine 3',5'-cyclic phosphorothioate [(S)-p-cAMPS]. These findings demonstrate that elevation of cAMP in RAW 264.7 cells by rolipram decreases TNF synthesis and increases NO formation.