期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 144, 期 5, 页码 1265-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.06.036
关键词
Prostaglandin E-2; prostaglandin E-2 receptor; thymic stromal lymphopoietin; IL-33; protease-activated receptor 2
资金
- Japan Society for the Promotion of Science KAKENHI [JP19K08790, JP15H05906, 263395]
- Japan Agency for Medical Research and Development (AMED) [19ek0410062s0201, 16ek0410011h0003, 16he0902003h0002]
- Practical Research Project for Allergic Diseases and Immunology from AMED [19ek0410040h0003]
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-2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 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-2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
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