INTERACTIONS BETWEEN CAMP-DEPENDENT AND CGMP-DEPENDENT PROTEIN-KINASEINHIBITORS AND PHOSPHODIESTERASE-IV INHIBITORS ON ARACHIDONATE RELEASE FROM HUMAN MONOCYTES

The effects of specific inhibitors of cAMP-dependent protein kinase (P KA) and cGMP-dependent protein kinase (PKG) on the inhibitory activity of phosphodiesterase (PDE) type IV inhibitors and of the cell permeab le analogue of cAMP, db-cAMP, were investigated on fMLP-induced arachi donate release from human monocytes. When monocytes were preincubated with the combined PKA/PKG inhibitor H8 (10(-6) to 10(-4) M) or the sel ective PKG inhibitor Rp-8-cpt-cGMPs (10(-6) to 10(-4) M) a concentrati on-dependent reduction of the inhibitory effect of db-cAMP (10(-3) M), rolipram (10(-5) M) and Ro 20-1724 (10(-5) M) was noted. When monocyt es were preincubated with the selective PKA inhibitor H89 (10(-6) to 1 0(-4) M), only a small inhibition of the effect of db-cAMP and no inhi bition of the effects of rolipram and Ro 20-1724 were observed. The pr esent data indicate that db-cAMP and PDE IV inhibitors elicit an in vi tro anti-inflammatory activity by a PKA-independent mechanism, which d o not appear to be mainly mediated via the PKG activation.