Topical Application of a PDE4 InhibitorAmeliorates Atopic Dermatitis throughInhibition of Basophil IL-4 Production

gyemin noh

Abstract

Phosphodiesterase 4 inhibitors have been approved for the treatment of atopic dermatitis. However, the
cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. In this
study, we addressed this unsolved issue by analyzing the action of difamilast, a novel phosphodiesterase 4
inhibitor, on an oxazolone-induced skin allergic inflammation commonly used as a mouse model of atopic
dermatitis. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4
expression even when the treatment commenced 4 days after the initiation of oxazolone challenge, showing
its therapeutic effect on atopic dermatitis. IL-4edeficient mice displayed milder skin inflammation than did
wild-type mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in
mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act
on basophils. Notably, basophils accumulating in the skin lesion showed highly upregulated expression of
Pde4b encoding the B subtype of the phosphodiesterase 4 family. Difamilast suppressed IL-4 production from
basophils activated in vitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate atopic dermatitis inflammation through the suppression of basophil IL-4 production in the skin lesion.

Keywords: Allergic inflammation, Difamilast, ERK, Mouse model, PDE4B