Modulation of Cytokine Production by Cyclic Adenosine Monophosphate Analogs in Human Leukocytes

Abstract

Cyclic adenosine monophosphate (cAMP) 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). Cell-permeable cAMP analogs 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 N(6)-benzoyladenosine-cAMP (6-Bnz-cAMP) and 8-pCPT-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 interleukin-10 (IL-10) in lipopolysaccharide-activated T-cell-depleted peripheral blood mononuclear cells, whereas the production of IL-1β, tumor necrosis factor α, 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. Further, 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 open up therapeutic possibilities using selective activators or inhibitors of EPAC or PKA.

Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway

“…This anti-inflammatory effect of torbafylline is in agreement with previous findings that torbafylline and pentoxifylline attenuated inflammatory cytokines in a number of animal models of wasting including cancer, sepsis and diabetes (Baviera et al, 2007;Breuillé et al, 1993;Combaret et al, 2002). The mechanism by which torbafylline attenuates the mRNA expression of inflammatory cytokines has not been investigated in the present investigations, but published reports suggest that cAMP may inhibit IL-6 and TNFa through independent pathways involving downstream elements, Epac (Metrich et al, 2010) and PKA (Gerlo et al, 2010), respectively (Fig. 7).…”

“…Epac/RAP activates multiple pathways involving PI3K/Akt. Activation of Epac and PKA also inhibits the production of IL-6 (Metrich et al, 2010) and TNFa (Gerlo et al, 2010), respectively. Activation of PI3K/ Akt/GSK3b pathway has been shown to contribute to the attenuation of muscle atrophy (Li et al, 2005), but the mechanism remains unclear.…”

Higher TNFα responses in young males compared to females are associated with attenuation of monocyte adenylyl cyclase expression

“…A main effect of cAMP signaling is a strong attenuation of proinflammatory TNFa, but many other inflammatory mediators are also affected by cAMP [25,26]. The cAMP signal not only modulates inflammatory cytokine release from macrophages, but has a range of effects on other immune cells.…”

Cyclic AMP: a selective modulator of NF-κB action

“…Although in many cases the alternative cAMP effectors remain to be identified, the guanine exchange proteins directly activated by cAMP (EPAC-1 and EPAC-2) are possible effector candidates [23,24]. Upon binding of cAMP, the EPACs elicit downstream responses via activation of the small Raslike GTPase Rap-1 and, moreover, they have recently been implicated as regulators of monocyte and macrophage function [25][26][27]. Finally, in specialized tissues such as olfactory neurons, cAMP can directly activate cyclic nucleotide-gated ion channels [28].…”