Superiority of combined phosphodiesterase PDE3/PDE4 inhibition over PDE4 inhibition alone on glucocorticoid- and long-acting β2-adrenoceptor agonist-induced gene expression in human airway epithelial cells

Mol Pharmacol. 2015 Jan;87(1):64-76. doi: 10.1124/mol.114.093393. Epub 2014 Oct 16.

Abstract

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 ICSs 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 with inhibiting either PDE alone. In respect to 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 fide 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 proinflammatory 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Cell Line
  • Drug Synergism
  • Drug Therapy, Combination
  • Epithelial Cells / drug effects
  • Ethanolamines / pharmacology
  • Formoterol Fumarate
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology*
  • Humans
  • Phosphodiesterase 3 Inhibitors / pharmacology*
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Respiratory System / cytology
  • Respiratory System / drug effects*
  • Transcription, Genetic / drug effects

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Ethanolamines
  • Glucocorticoids
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Formoterol Fumarate