CHARACTERIZATION OF CAMP-DEPENDENT INHIBITION OF LPS-INDUCED TNF-ALPHA PRODUCTION BY ROLIPRAM, A SPECIFIC PHOSPHODIESTERASE-IV (PDE-IV) INHIBITOR

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tis sue injury by eliciting the release of toxic factors from reticuloendo thelial cells. One of the principal endogenous factors involved in thi s process is tumor necrosis factor alpha (TNF alpha). In this study, i nhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production b y human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF al pha production by rolipram was 0.1 mu M, whereas production of IL-1 be ta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhi bition of TNF alpha production by rolipram was associated with an elev ation of intracellular cAMP, consistent with a mechanism involving pho sphodiesterase inhibition. Rolipram was efficacious in suppressing LPS -induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational l evels. Rolipram inhibited TNF alpha production in vivo in a rat endoto xemia model. Collectively, these data suggest that the prototypic inhi bitor of PDE IV isozyme, rolipram, can effectively and selectively inh ibit LPS-induced TNF alpha production through elevation of intracellul ar cAMP.