LSC 2011 Abstract: Potential anti-inflammatory role of the cAMP effectors Epac and PKA in COPD

Cigarette smoke-induced release of pro-inflammatory cytokines such as interleukin-8 (IL-8) from airway smooth muscle (ASM) cells may contribute to the development of chronic obstructive pulmonary disease (COPD). Here, we investigated the role of the cAMP-effectors Epac and PKA on cigarette smoke extract (CSE)-induced IL-8 release by human ASM cells as well as the potential signalling mechanisms involved. Additionally, the impact of CSE on Epac and PKA expression was evaluated. CSE-induced IL-8 release from ASM was reduced by the β 2 -agonist fenoterol, the Epac activator 8-pCPT-2'- O -Me-cAMP and the PKA activator 6-Bnz-cAMP. CSE induced IκBα degradation and p65 nuclear translocation, processes that were primarily reversed by the Epac activator 8-pCPT-2'- O -Me-cAMP. In addition, CSE increased extracellular signal-regulated kinase (ERK) phosphorylation, which was selectively reduced by the PKA activator 6-Bnz-cAMP. Furthermore, CSE decreased Epac1 expression, but had no effects on Epac2 and PKA expression. Importantly, we observed reduced Epac1 expression in lung tissue from COPD patients. In conclusion, our data indicate that Epac and PKA differentially decrease CSE-induced IL-8 release by ASM cells, via inhibition of NF-κB and ERK signalling, respectively. Our findings further indicate that cigarette smoke exposure may reduce anti-inflammatory effects of cAMP in the airways via down-regulation of Epac1.