Interactions between cAMP- and cGMP-dependent protein kinase inhibitors and phosphodiesterase IV inhibitors on arachidonate release from human monocytes

Abstract The effects of specific inhibitors of cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) on the inhibitory activity of phosphodiesterase (PDE) type IV inhibitors and of the cell permeable analogue of cAMP, db-cAMP, were investigated on fMLP-induced arachidonate release from human monocytes. When monocytes were preincubated with the combined PKA/PKG inhibitor H8 (10 −6 to 10 −4 M) or the selective PKG inhibitor Rp-8-cpt-cGMPs (10 −6 to 10 −4 M) a concentration-dependent reduction of the inhibitory effect of db-cAMP (10 − M), rolipram (10 −5 M) and Ro 20-1724 (10 −5 M) was noted. When monocytes were preincubated with the selective PKA inhibitor H89 (10 −6 to 10 −4 M), only a small inhibition of the effect of db-cAMP and no inhibition of the effects of rolipram and Ro 20–1724 were observed. The present data indicate that db-cAMP and PDE IV inhibitors elicit an in vitro anti-inflammatory activity by a PKA-independent mechanism, which do not appear to be mainly mediated via the PKG activation.