Anti-Inflammatory Role of the cAMP Effectors Epac and PKA: Implications in Chronic Obstructive Pulmonary Disease

Abstract

Cigarette smoke-induced release of pro-inflammatory cytokines including interleukin-8 (IL-8) from inflammatory as well as structural cells in the airways, including airway smooth muscle (ASM) cells, may contribute to the development of chronic obstructive pulmonary disease (COPD). Despite the wide use of pharmacological treatment aimed at increasing intracellular levels of the endogenous suppressor cyclic AMP (cAMP), little is known about its exact mechanism of action. We report here that next to the β2-agonist fenoterol, direct and specific activation of either exchange protein directly activated by cAMP (Epac) or protein kinase A (PKA) reduced cigarette smoke extract (CSE)-induced IL-8 mRNA expression and protein release by human ASM cells. CSE-induced IκBα-degradation and p65 nuclear translocation, processes that were primarily reversed by Epac activation. Further, CSE increased extracellular signal-regulated kinase (ERK) phosphorylation, which was selectively reduced by PKA activation. CSE decreased Epac1 expression, but did not affect Epac2 and PKA expression. Importantly, Epac1 expression was also reduced in lung tissue from COPD patients. In conclusion, Epac and PKA decrease CSE-induced IL-8 release by human ASM cells via inhibition of NF-κB and ERK, respectively, pointing at these cAMP effectors as potential targets for anti-inflammatory therapy in COPD. However, cigarette smoke exposure may reduce anti-inflammatory effects of cAMP elevating agents via down-regulation of Epac1.

A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

“…In agreement with our previous findings (26), CSE induced IL-8 release from hTERT ASM cells, with the levels in cell culture supernatant being increased by 77 Ϯ 21% compared with basal levels in untreated cultures (P Ͻ 0.01, Fig. 6, A and B).…”

“…6B). Similarly, as we observed previously (26), selective pharmacological activation of Epac with 8-pCPT (100 M) decreased CSE-induced IL-8 release (P ϭ 0.07, Fig. 6B).…”

“…CSE was prepared using 3R4F research cigarettes (Reference Cigarette Program, University of Kentucky) (4) as described previously (25,26). In short, two cigarettes were combusted using a peristaltic pump (Watson Marlow 323 E/D) in to 25 ml of serum-free medium; this was designated 100% CSE and was diluted to 15% CSE using serum-free medium.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…by growth factors. This process involves PKA and Epac [162] that apparently act synergistically [163,164]. The activation of either Epac or PKA decreased cigarette smoke extract--induced IL--8 mRNA expression and IL--8 release from human ASM cells by a mechanism involving ERK and NFƙB signaling [162].…”

“…As there is no curative treatment existing for COPD, the medical need for pharmacological intervention is high. Local PKA signaling might be an appropriate pharmacological target for anti--inflammatory therapy of COPD [162].…”