Murakami-Satsutani Naoko, Ito Tomoki, Nakanishi Takahisa, Inagaki Noriko, Tanaka Akihiro, Vien Phan Thi Xuan, Kibata Kayoko, Inaba Muneo, Nomura Shosaku
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
First Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Allergol Int. 2014;63(3):443-455. doi: 10.2332/allergolint.13-OA-0672. Epub 2015 Feb 27.
In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.
Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.
IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.
IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.
在Th2免疫反应中，胸腺基质淋巴细胞生成素（TSLP）通过诱导树突状细胞（DCs）上的OX40配体（OX40L）发挥关键作用，而OX40L是诱导Th2细胞介导的过敏级联反应的触发因素。因此，TSLP-DC-OX40L轴可能是特应性皮炎和哮喘炎症级联反应中的主要途径。由上皮细胞产生的白细胞介素33（IL-33）与Th2免疫反应及过敏性疾病的发病机制有关。然而，IL-33在Th2极化的TSLP-DC-OX40L轴中的作用仍 largely难以捉摸。我们聚焦于IL-33促进OX40L介导的Th2反应的能力。
在存在IL-33的情况下，用重组OX40L或经TSLP处理的DCs（TSLP-DCs）刺激纯化的人初始或记忆CD4+ T细胞，并检测经致敏的T细胞产生的细胞因子。我们还对特应性皮炎患者的淋巴结和皮肤标本中IL-33的表达进行了免疫组织化学分析。
IL-33通过增加IL-5、IL-9和IL-13的产生，显著增强了初始T细胞对TSLP-DCs驱动或OX40L驱动的Th2反应以及CRTH2+ CD4+ Th2记忆细胞的Th2功能特性。此外，IL-33不仅在特应性皮炎患者的皮肤病变中，而且在其淋巴结的上皮细胞核中表达，提示其在适应性T细胞致敏阶段发挥特殊作用。
IL-33作为TSLP-DC-OX40L轴的正向调节因子，启动并维持Th2细胞介导的炎症反应，因此，它将成为治疗过敏性疾病的新治疗靶点。
