Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Allergy Clin Immunol. 2019 Nov;144(5):1265-1273.e9. doi: 10.1016/j.jaci.2019.06.036. Epub 2019 Jul 11.
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.
We sought to elucidate the functions of prostanoids in the development of AD.
The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line.
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.
Prostaglandin E-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
特应性皮炎（AD）是一种常见的 2 型免疫慢性炎症性皮肤疾病。角朊细胞衍生的细胞因子，包括胸腺基质淋巴细胞生成素（TSLP）和 IL-33，被认为可诱导 AD 的发展。前列腺素，一种脂质介质家族，在 AD 病变中的产生增加。然而，它们的生理功能仍有待阐明。
我们旨在阐明前列腺素在 AD 发展中的作用。
我们通过重复应用半抗原和 PAM212 诱导的 AD 小鼠模型以及角质形成细胞系研究了前列腺素的作用。
应用阻断前列腺素合成的吲哚美辛可导致 AD 模型皮肤中 TSLP 和 IL-33 的产生增加，血清 IgE 水平升高，皮肤炎症加重。在 TSLP 受体缺陷小鼠中，皮肤炎症减轻，但在 IL-33 缺陷小鼠中则没有减轻，并且在 TSLP 受体缺陷小鼠中，吲哚美辛增强的 2 型免疫反应被消除。吲哚美辛在体外增加角质形成细胞中蛋白酶激活受体 2 介导的 TSLP 产生，前列腺素 E 通过下调蛋白酶激活受体 2 的表面表达，通过其受体（前列腺素 E 受体 [EP2]）逆转 TSLP 水平的增加。EP2 激动剂可消除吲哚美辛增强的皮肤 TSLP 产生和 2 型免疫反应，而 EP2 拮抗剂可增强皮肤 TSLP 产生和 2 型免疫反应。
前列腺素 E-EP2 信号通过抑制 TSLP 表达负调节小鼠类似 AD 的皮肤炎症。
