Adrenaline enhances LPS-induced IL-10 synthesis: evidence for protein kinase A-mediated pathway

The aim of the present study was to investigate the role of cAMP in enhanced IL-10 synthesis in human mononuclear cells. Adrenaline is known to act via the alpha- and beta-adrenergic receptors which are coupled to adenylyl cyclase. The effects of cAMP elevation on IL-10 synthesis were studied at the protein level by ELISA and at the level of mRNA by RT/PCR. In this in vitro model adrenaline enhanced the LPS-induced synthesis of IL-10 with parallel suppression of TNF synthesis. These effects were demonstrated both at the protein level and the level of mRNA. To analyze the role of cAMP we antagonized this effect by application of(Rp)-cAMPS, a diastereomer of adenosine-3',5'-cyclic phosphorothioate, known to inhibit competitively the cAMP-induced activation of protein kinase A. Simultaneous addition of adrenaline and (Rp)-cAMPS Zed to a reversal of IL-10 synthesis to values induced by LPS stimulation alone. The kinetic analysis in LPS-stimulated mononuclear cells revealed a significant delay of IL-10 synthesis starting after 7 h compared with TNF synthesis which showed the first significant increase at 90 min. Finally, the combination of adrenaline and exogenous IL-10 led to a more pronounced suppression of TNF synthesis after LPS stimulation compared to suppression by IL-10 or adrenaline alone. The present results suggest the role of protein kinase A activation-for adrenaline-induced IL-10 synthesis in human mononuclear cells. Additionally, based on the kinetic analysis and further experiments described in the literature, endogenous IL-IO could contribute to the adrenaline-induced suppression of TNF synthesis after prolonged incubation. These in vitro results could explain the suppression of TNF plasma concentration after parallel infusion of LPS and epinephrine compared to LPS infusion alone as has been demonstrated in a first human study. (C) 1998 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.