Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mainly caused by cigarette smoking (CS). Compartmentalization of cAMP signaling regulates cellular responses to (local) changes in cAMP levels. In this respect, A-kinase anchoring proteins (AKAPs) compartmentalize cAMP signaling by differentially docking proteins involved in cAMP signaling, including β2-adrenoceptors and the cAMP effectors PKA and Epac. Interestingly, AKAP79 (aka AKAP5) is involved in β2-adrenoceptor desensitization, which is opposed by AKAP250 (aka AKAP12). Here we studied the expression pattern and functions of AKAPs in regulating inflammatory cytokine release and the responsiveness to β2-agonists.
AKAP79, AKAP250 and AKAP450 (aka AKAP9) are expressed in human airway smooth muscle (hASM). Treatment with CS downregulated AKAP250 and (to a lesser extent) AKAP79, but not AKAP450. In lung tissue of COPD patients all these AKAPs were downregulated. In hASM cells, CS-induced IL-8 release was dose-dependently decreased by the β2-agonist fenoterol as well as by direct activation of PKA and (only marginally) of Epac. CS-induced IL-8 release was augmented by the PKA-binding blocking peptide st-Ht31, a generic AKAP inhibitor. Importantly, in the presence of st-Ht31 fenoterol was unable to reduce CS-induced IL-8, whereas the PKA activator was still fully effective.
In conclusion, AKAPs are expressed in the airways and coordinate the communication between β2-adrenoceptors and cAMP effectors in order to reduce CS-induced inflammation. Since AKAP expression is altered in COPD, AKAPs could contribute to the pathophysiology of this disease. Supported by Stichting Astma Bestrijding and a Rosalind Franklin Fellowship.
- © 2011 ERS