Dexamethasone Inhibits Synergistic Induction of PDE4B Expression by Roflumilast and Bacterium NTHi

Abstract

Phosphodiesterase 4B (PDE4B) plays an important role in inflammation. Recently we have reported that roflumilast as a PDE4-selective inhibitor, synergizes with nontypeable Haemophilus influenzae (NTHi) to up-regulate PDE4B expression in vitro and in vivo. Clinical evidence and our previous results suggest that synergistic induction of PDE4B could be counterproductive for suppressing inflammation or may contribute to tolerance to roflumilast. We thus investigated if dexamethasone inhibits the synergistic induction of PDE4B by roflumilast and NTHi as well as inflammation. Here, dexamethasone markedly suppressed the synergistic induction of PDE4B in human lung epithelial cells and in vivo. We also found that dexamethasone further suppressed NTHi-induced inflammatory response in vitro and in vivo. Moreover, Compound A, as a dissociating non-steroidal glucocorticoid receptor (GR) ligand, inhibited the synergistic induction of PDE4B, thereby suggesting the requirement of dexamethasone-mediated GR activation in the suppression of PDE4B expression. Taken together, our data suggest that dexamethasone may help attenuate inflammation and tolerance through suppressing the PDE4B expression in chronic obstructive pulmonary disease (COPD) patients using roflumilast.

Long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) sponges microRNA-124-3p to up-regulate phosphodiesterase 4B (PDE4B) to accelerate the progression of Parkinson’s disease

“…As reported, PDE4 (cAMP-specific) features prominently in the central nervous system, and among the 11 PDE family members. PDE4B, belonging to PDE4, is crucial in regulating neuroinflammation, and PDE4B inhibitors have neuroprotective effects [42][43][44]. Reportedly, miR-124-3p represses the activity of mTOR signaling by repressing PDE4B expression, and is crucial on neuronal inflammation caused by brain injury [45].…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…Researchers subsequently invented apremilast, a newer third-generation PDE4 inhibitor, by using a recognized functional pharmacophore of earlier PDE4 inhibitors and adding a series of active groups in order to reduce side effects and optimize pharmaceutical effects (23). However, clinical evidence suggests that treatment with repeated dosing of roflumilast may lead to the development of tachyphylaxis or tolerance for roflumilast through up-regulation of PDE4B expression (24). Nevertheless, to date, there have been no studies reporting an effective new PDE4D inhibitor without side effects.…”