Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2019-07-11 , DOI: 10.1016/j.jaci.2019.06.036 Yu Sawada 1 , Tetsuya Honda 2 , Satoshi Nakamizo 2 , Saeko Nakajima 2 , Yumi Nonomura 2 , Atsushi Otsuka 2 , Gyohei Egawa 2 , Tomohiro Yoshimoto 3 , Motonobu Nakamura 4 , Shuh Narumiya 5 , Kenji Kabashima 6
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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 E2 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 E2–EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
中文翻译：
前列腺素E2（PGE2）-EP2信号通过抑制胸腺基质淋巴细胞生成素的表达，负调控鼠类特应性皮炎样皮肤炎症。
背景
特应性皮炎（AD）是2型免疫力的常见和慢性炎症性皮肤病。包括胸腺基质淋巴细胞生成素（TSLP）和IL-33在内的角质形成细胞衍生的细胞因子被认为可诱导AD的发展。AD病变中类脂介导物家族前列腺素的产生增加。但是，它们的生理功能仍有待阐明。
目标
我们试图阐明前列腺素在AD发展中的功能。
方法
在反复使用半抗原和角质形成细胞系PAM212诱导的AD小鼠模型中，研究了类前列腺素的作用。
结果
消炎痛的应用可阻止前列腺素的合成，从而导致皮肤中TSLP和IL-33的产生增加，血清IgE水平升高，并加剧该AD模型的皮肤炎症。TSLP受体缺陷型小鼠的皮肤炎症得到缓解，而IL-33缺陷小鼠的炎症没有减弱，TSLP受体缺陷小鼠的消炎痛增强的2型免疫反应被消除。吲哚美辛增加角质形成细胞中蛋白酶活化受体2介导的TSLP产生在体外，和前列腺素E 2通过其受体时，前列腺素E逆转TSLP水平增加2 受体（EP2），通过下调蛋白酶激活受体2的表面表达。施用EP2激动剂可消除消炎痛增强的TSLP产生和皮肤中的2型免疫反应，而EP2拮抗剂引起TSLP产生和2型免疫的增强。皮肤中的反应。
结论
前列腺素E 2 -EP2信号通过抑制TSLP表达负调控鼠类AD皮肤炎症。
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