PT  - JOURNAL ARTICLE
AU  - Hawazen BinMahfouz
AU  - Dong Yan
AU  - Bibhusana Borthakur
AU  - Tresa George
AU  - Mark A Giembycz
AU  - Robert Newton
TI  - Superiority of Combined PDE3/PDE4 Inhibition Over PDE4 Inhibition Alone on Glucocorticoid- And long-acting β<sub>2</sub>-adrenoceptor Agonist-induced Gene Expression in Human Airway Epithelial Cells
AID  - 10.1124/mol.114.093393
DP  - 2014 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.093393
4099  - http://molpharm.aspetjournals.org/content/early/2014/10/16/mol.114.093393.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/10/16/mol.114.093393.full
AB  - Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting β2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICS alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared to inhibiting either PDE alone. In respect of cAMP-dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element-dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3 inhibition. Overall similar effects were described for bona fides genes, including RGS2, CD200 and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the pro-inflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize and prolong the effects of LABA/ICS combination therapies.