Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Allergy. 2018 Sep;73(9):1881-1891. doi: 10.1111/all.13437.
Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal.
We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in AD patients.
We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue-resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL-24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite-treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin-deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from AD patients.
The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD.
屏障功能障碍是特应性皮炎（AD）的一个重要特征，其中涉及到白细胞介素 4（IL-4）和白细胞介素 13（IL-13）这两种 2 型细胞因子。由 IL-4 或 IL-13 诱导的基质细胞蛋白 periostin 在过敏性皮肤炎症（包括屏障功能障碍）的发病机制中起着至关重要的作用。然而，periostin 如何在 IL-13 信号的下游导致屏障功能障碍仍然难以捉摸。
我们使用 DNA 微阵列系统地鉴定了 periostin 依赖性表达谱。然后，我们研究了 IL-24 是否下调了 IL-13 信号下游的丝聚蛋白表达，以及 IL-13 诱导的 IL-24 表达和 IL-24 诱导的丝聚蛋白表达下调是否依赖于 JAK/STAT 通路。为了进一步研究体外研究结果的意义，我们研究了在螨处理的小鼠和 AD 患者中 IL-24 和 STAT3 的表达。
我们鉴定出 IL-24 是一种 IL-13 诱导的分子，其表达依赖于 periostin。角质形成细胞是 IL-13 以 periostin 依赖的方式刺激的主要 IL-24 产生组织驻留细胞，通过 STAT6 发挥作用。IL-24 通过 STAT3 显著地下调丝聚蛋白的表达，导致 IL-13/periostin 通路下游的屏障功能障碍。野生型螨处理的小鼠在表皮中显示出显著增强的 IL-24 表达和 STAT3 的激活，而在 STAT6 缺陷型和 periostin 缺陷型小鼠中则消失，表明这些事件依赖于 STAT6 和 periostin。此外，在取自 AD 患者的皮肤组织中，IL-24 的表达在表皮中增强。
IL-13/periostin 通路诱导角质形成细胞产生 IL-24，在 AD 中的屏障功能障碍中发挥重要作用。
