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.