Phellopterin alleviates atopic dermatitis-like inflammation and suppresses IL-4-induced STAT3 activation in keratinocytes

Anti-inflammation medication is one of the most important treatment for people with atopic dermatitis (AD) which presents persistent type 2 inflammation in skin lesions. Interaction between activated keratinocytes and immune cells in AD skin lesions amplifies inflammatory signaling by augmenting production of cytokines, such as keratinocyte-derived thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33). Phellopterin is a bioactive compound isolated from ethanol extract of Angelica dahurica root which has been traditionally used for AD therapy in China. In the present study, we showed that Phellopterin possessed anti-type 2 inflammation activity and alleviated AD-like phenotypes including reduction in serum immunoglobulin E (IgE) levels and infiltration of eosinophils and mast cells in the AD-like skin lesions. Further molecular analysis found that Phellopterin suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705, and the expression of TSLP and IL-33 in epidermal keratinocytes of AD-like lesions. In vitro studies in cultured human keratinocytes demonstrated that STAT3 was required for interleukin-4 (IL-4)-induced overexpression of TSLP and IL-33. Phellopterin inhibited IL-4-induced activation of STAT3, which leaded to suppress the STAT3mediated transcription of TSLP and IL-33. Our study suggested that Phellopterin is an active compound with bioactivities of anti- type 2 inflammation and STAT3 inactivation, thus allowing to be a promising candidate for AD topical therapy.