Phosphodiesterase 4 inhibitors and db-cAMP inhibit TNF-α release from human mononuclear cells. Effects of cAMP and cGMP-dependent protein kinase inhibitors

摘要

We investigated 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 4 inhibitors and of the cell permeable analogue of cAMP, db-cAMP on LPS-induced TNF-α release from human mononuclear cells. Incubation from 30 min of mononuclear cells with dbcAMP (10⁻⁵ to 10⁻³ M), rolipram (10⁻⁹ M to 10⁻⁵ M) or Ro 20-1724 (10⁻⁹ M to 10⁻⁵ M) significantly inhibited LPS-induced TNF-α release. When mononuclear cells were preincubated for 30 min with the selective PKA inhibitor, H89 (10⁻⁴ M), but not with the selective PKG inhibitor, Rp-8-pCPT-cGMPs (10⁻⁴ M), a significant reduction of the inhibitory effect of db-cAMP was noted. Thirty min incubation of mononuclear cells with Rp-8-pCPT-cGMPs induced a significant reduction of the inhibitory activities of both rolipram and Ro 20-1724 (10⁻⁹ to 10⁻⁵ M) on LPS-induced TNF-α release, whereas H89 elicited a moderate, but significant inhibition. The present data indicate that db-cAMP inhibits TNF-α release from human mononuclear cells through a PKA-dependent mechanism. In contrast, PDE 4 inhibitors elicit their in vitro anti-inflammatory activities via a PKG-dependent rather than PKA-dependent activation.