Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells

Abstract

Background: Phosphodiesterase (PDE4) inhibitors prevent breakdown of cAMP and affect the increase in cellular levels of cAMP, which is known to regulate immune cell functions. Because IL-4 plays a causal role in the pathogenesis of allergic disorders, we were interested to study the modulatory mechanisms of a PDE4 inhibitor, rolipram, in IL-4-mediated signaling in T cells. Methods: Human peripheral T cells were stimulated with IL-4 in combination with rolipram, and RT-PCR was performed using primers specific for IL-5. To monitor activation of transcription factors, immunostaining was employed. Results: Rolipram or a cAMP-analogue, 8-Br-cAMP, significantly downregulated IL-4-induced expression of IL-5 mRNA. The rolipram-induced inhibition of IL-5 mRNA was mediated by activation of protein kinase A (PKA), because rolipram-downregulated mRNA expression of IL-5 was restored by PKA inhibitors. Immunostaining revealed that rolipram interfered with IL-4-induced nuclear translocation of activator protein (AP)-1 components. Conclusions: This is the first demonstration of suppression of IL-4 signaling by PDE4 inhibitors via prevention of nuclear translocation of AP-1.

New era of biologic therapeutics in atopic dermatitis

“…[145,146140,141] Inhibitors of PDE have shown clinical benefit when used topically in AD patients. [148143] An open label study with Apremilast, a novel oral PDE4 inhibitor that is currently in phase 2 clinical trials for psoriasis, was given to 16 adult patients with moderate to severe AD, in two cohorts of 6 patients receiving a lower dose of 20 mg twice daily and 10 on the higher dose of 30 mg twice daily. [149144] The clinical responses seen at 6 months showed a reduction of approx 50% in the EASI score in the cohort obtaining the highest dosing.…”