Prostaglandin E (PGE)-EP2 signaling negatively regulates murine atopic dermatitis-like skin inflammation by suppressing thymic stromal lymphopoietin expression.

BACKGROUND

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified.

OBJECTIVES

We sought to elucidate the functions of prostanoids in the development of AD.

METHODS

The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line.

RESULTS

Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes in vitro, and prostaglandin E reversed the increase in TSLP levels through its receptor, the prostaglandin E receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin.

CONCLUSION

Prostaglandin E-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.