IL-33 induces Egr-1-dependent TSLP expression via the MAPK pathways in human keratinocytes
IL-33 induces Egr-1-dependent TSLP expression via the MAPK pathways in human keratinocytes
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DOI：
10.1111/exd.12788
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发表时间：
2015-11-01
影响因子：
3.6
通讯作者：
Son, Sang Wook
中科院分区：
文献类型：
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作者：
Ryu, Woo-In;Lee, Hana;Son, Sang Wook
特应性皮炎（AD）是一种以辅助性T细胞2型（Th 2）免疫应答为主的慢性炎症性皮肤病。Th 2细胞因子、白细胞介素（IL）-33和胸腺基质淋巴细胞生成素（TSLP）在AD发病中起重要作用。IL-33在AD中高度表达，但其在AD中的作用尚未完全了解。为了进一步确定IL-33在AD中的作用，我们研究了角质形成细胞中IL-33诱导的TSLP的表达。本研究揭示IL-33诱导人角质形成细胞中TSLP的表达。早期生长反应蛋白1（Egr）-1是一种炎症转录因子，由IL-33诱导。角质形成细胞中IL-33介导的TSLP诱导被丝裂原活化蛋白激酶（MAPK）抑制剂或针对Egr-1的小干扰RNA抑制。染色质免疫沉淀（ChIP）分析表明Egr-1直接参与IL-33介导的TSLP诱导。总之，这些发现表明IL-33可能通过Egr-1依赖性机制通过ERK 1/2、JNK和p38激活角质形成细胞来增加TSLP表达。提示IL-33-ERK/JNK/p38/Egr-1/TSLP轴参与了过敏性皮肤Th 2炎症的发生，可能成为一个新的治疗靶点。
Atopic dermatitis (AD) is a chronic inflammatory skin disease in which T-helper type 2 (Th2)-type immune responses are dominant. Th2 cytokine, interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) have been suggested to have an important role in AD. IL-33 is highly expressed in AD, but its role in AD has not yet been fully understood. To further identify the role of IL-33 in AD, we investigated the expression of TSLP induced by IL-33 in keratinocytes. This study revealed that IL-33 induced TSLP expression in human keratinocytes. Early growth response protein 1 (Egr)-1, which is an inflammatory transcriptional factor, is induced by IL-33. IL-33-mediated TSLP induction in keratinocytes was suppressed by treatment with mitogen-activated protein kinase (MAPK) inhibitors or small interfering RNA against Egr-1. Chromatin immunoprecipitation (ChIP) assay indicated the direct involvement of Egr-1 in IL-33-mediated TSLP induction. Taken together, these findings indicate that IL-33 may increase TSLP expression through an Egr-1-dependent mechanism via ERK1/2, JNK and p38 activation in keratinocytes. These data suggest that the IL-33-ERK/JNK/p38/Egr-1/TSLP axis is involved in allergic skin Th2 inflammation, and it may be a novel therapeutic target.