Inhibitors of Phosphodiesterase 4, but Not Phosphodiesterase 3, Increase β2-Agonist-Induced Expression of Antiinflammatory Mitogen-Activated Protein Kinase Phosphatase 1 in Airway Smooth Muscle Cells.

β2-agonists are principally used in asthma to provide bronchodilation; however, they also have antiinflammatory properties, due, in part, to their ability to up-regulate mitogen-activated protein kinase phosphatase (MKP) 1 in a cAMP-dependent manner. Phosphodiesterases (PDEs) are attractive targets for potentiating the antiinflammatory response. There are 11 subfamilies of PDE enzymes; among these, inhibition of PDE3 and PDE4 are the main targets for airway smooth muscle (ASM). PDE enzymes are important intracellular regulators that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate to their inactive forms. Given that MKP-1 is cAMP dependent, and inhibition of PDE acts to increase β2-agonist-induced cAMP, it is possible that the presence of PDE inhibitors may enhance β2-adrenoceptor-mediated responses. We address this herein by comparing the ability of a panel of inhibitors against PDE3 (cilostamide, cilostazol, milrinone) or PDE4 (cilomilast, piclamilast, rolipram) to increase cAMP, MKP-1 mRNA expression, and protein up-regulation in ASM cells induced in response to the β2-agonist formoterol. Our data show that inhibitors of PDE4, but not PDE3, increase β2-agonist-induced cAMP and induce MKP-1 mRNA expression and protein up-regulation. When cAMP was increased, there was a concomitant increase in MKP-1 levels and significant inhibition of TNF-α-induced CXCL8 (IL-8). This result was consistent with all PDE4 inhibitors examined but not for the PDE3 inhibitors. These findings reinforce cAMP-dependent control of MKP-1 expression, and suggest that PDE4 is the predominant PDE isoform responsible for formoterol-induced cAMP breakdown in ASM cells. Our study is the first to demonstrate that PDE4 inhibitors augment antiinflammatory effects of β2-agonists via increased MKP-1 expression in ASM cells.