Rolipram, salbutamol and prostaglandin E2 suppress TNFalpha release from human monocytes by activating Type II cAMP-dependent protein kinase.

The extent to which cAMP-dependent protein kinase (PKA) mediates the inhibitory effects of cAMP-elevating drugs on tumour necrosis factor (TNF) alpha release from lipopolysaccharide (LPS)-stimulated human monocytes is equivocal. Here, we have investigated the role of this kinase by exploiting the ability of certain novel cAMP analogues to inhibit or activate PKA and the recently described cAMP-guanine nucleotide-exchange factors (GEFs). Pre-treatment of monocytes with Rp-8-Br-cAMPS, a selective inhibitor of Type I PKA that has no effect on basal or stimulated Rap1 (a downstream effector of cAMP-GEFs) activity, potentiated LPS-induced TNFalpha output but had little or no effect on the suppression of this cytokine effected by rolipram (a PDE4 inhibitor), prostaglandin (PG) E2 and salbutamol (a beta2-adrenoceptor agonist).