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 (10−5to 10−3M), rolipram (10−9M to 10−5M) or Ro 20-1724 (10−9M to 10−5M) significantly inhibited LPS-induced TNF-α release. When mononuclear cells were preincubated for 30 min with the selective PKA inhibitor, H89 (10−4M), but not with the selective PKG inhibitor, Rp-8-pCPT-cGMPs (10−4M), 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 (10−9to 10−5M) 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 theirin vitroanti-inflammatory activitiesviaa PKG-dependent rather than PKA-dependent activation.

[学科分类] 生理学与病理学