Modulation of cytokine production by cAMP-analogues in human leukocytes

Cyclic-AMP is a well-known second messenger that operates through different signaling molecules including protein kinase A (PKA) and guanine exchange proteins directly activated by cAMP (EPAC). It has been shown that cell-permeable cAMP analogues such as 8-(4-chloro-phenyl-thio)-cAMP (8-pCPT-cAMP) modulate cytokine secretion by different leukocyte subsets, including T cells and monocytes. Since cAMP-modulating drugs such as phosphodiesterase inhibitors are being tested in inflammatory disorders such as asthma and chronic obstructive lung disease, it is important to obtain more insight into the regulation of cytokine production by cAMP. To address the signaling molecules involved in cAMP-mediated modulation of cytokine production, we used cAMP derivatives such as N6-benzoyladenosine-cAMP (6-Bnz-cAMP) and 8-(4-chloro-phenyl-thio)-2-O-methyl cAMP (8-pCPT-2'-O-Me-cAMP) which selectively activate either PKA or EPAC, respectively.
We show that in T cells, 6-Bnz-cAMP exerts similar globally inhibiting effects on cytokine secretion as 8-pCPT-cAMP, indicating that these effects are mediated by PKA. On the contrary, 8-pCPT-2'-O-Me-cAMP specifically inhibits the production of IL-10 in lipopolysaccharide (LPS)-activated T cell-depleted PBMC, whereas the production of IL-1?, IL-6, IL-8, TNF? and IL-12 is not or hardly affected. Inhibition by 8-pCPT-2'-O-Me-cAMP of IL-10 production was confirmed using purified monocytes. Furthermore, in B cells 6-Bnz-cAMP but not 8-pCPT-2'-O-Me-cAMP stimulated IL-10 production. In conclusion, cAMP stimulates IL-10 production via PKA in activated B cells, but inhibits IL-10 production in activated monocytes through EPAC.
We speculate that selective effects of PKA and EPAC on cytokine production in leukocyte subsets opens up therapeutic possibilities using selective activators or inhibitors of EPAC or PKA.