IL-4 Augments IL-31/IL-31 Receptor Alpha Interaction Leading to Enhanced Ccl 17 and Ccl 22 Production in Dendritic Cells: Implications for Atopic Dermatitis
IL-4 Augments IL-31/IL-31 Receptor Alpha Interaction Leading to Enhanced Ccl 17 and Ccl 22 Production in Dendritic Cells: Implications for Atopic Dermatitis
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DOI：
10.3390/ijms20164053
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发表时间：
2019-08-02
影响因子：
5.6
通讯作者：
Nakahara, Takeshi
中科院分区：
文献类型：
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作者：
Miake, Sho;Tsuji, Gaku;Nakahara, Takeshi
严重瘙痒是特应性皮炎（AD）的特征性特征，并与其活动密切相关。最近的研究表明，IL-31是AD瘙痒症的关键决定因素。据报道，抗IL-31受体α（IL-31 RA）抗体治疗在临床上可改善瘙痒，随后有助于AD疾病活动性的减弱。因此，IL-31被认为是调节瘙痒和AD疾病活动的重要细胞因子;然而，IL-31如何参与AD中的免疫应答仍在很大程度上未知。已有研究表明，来源于骨髓的表皮朗格汉斯细胞（LC）和真皮树突状细胞（DC）在AD的发病机制中起重要作用。LC和DC产生Ccl 17和Ccl 22，其化学吸引Th 2细胞，导致AD发展。因此，我们旨在阐明IL-31/IL-31 RA相互作用如何影响Ccl 17和Ccl 22的产生。为了验证这一点，我们分析了小鼠骨髓来源的DC（BMDCs）刺激与IL-4，一个重要的细胞因子在AD的发展。我们发现，IL-31 RA的表达上调IL-4刺激剂量依赖性的方式在BMDCs。此外，IL-31在IL-4存在下上调Ccl 17和Ccl 22的产生，而单独的IL-31刺激不产生Ccl 17和Ccl 22。提示IL-4介导IL-31 RA的表达，IL-31/IL-31 RA相互作用促进BMDCs产生Ccl 17和Ccl 22，从而促进AD患者Th 2偏移的免疫应答。由于我们之前报道过大豆焦油Glyteer（一种芳烃受体（AHR）配体）会损害BMDC中的IL-4/Stat 6信号传导，因此我们检查了Glyteer是否影响IL-4刺激诱导的IL-31 RA表达。Glyteer以剂量依赖性方式抑制IL-4刺激诱导的IL-31 RA表达上调。Glyteer还抑制由IL-4和IL-31刺激诱导的Ccl 17和Ccl 22的产生。总之，这些发现表明Glyteer治疗可能通过损害DC中的IL-31/IL-31 RA相互作用来改善AD疾病活动。
Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.