Mizuta Mao, Inoue Natsumi, Shimizu Masaki, Sakumura Naoto, Yokoyama Tadafumi, Kuroda Rie, Ikawa Yasuhiro, Sugimoto Naotoshi, Harada Kenichi, Yachie Akihiro, Wada Taizo
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
J Allergy Clin Immunol. 2023 Oct;152(4):940-948.e6. doi: 10.1016/j.jaci.2023.05.027. Epub 2023 Jun 22.
IL-18 and IL-1β play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS).
This study aimed to clarify the role of IL-18 and IL-1β in the pathogenesis of MAS.
We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1β, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1β, and combination (IL-18+IL-1β) groups.
Body weight was significantly decreased in the IL-1β and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels.
IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.
白细胞介素-18（IL-18）和白细胞介素-1β（IL-1β）在全身型幼年特发性关节炎及其危及生命的并发症巨噬细胞活化综合征（MAS）的发病机制中起核心作用。
本研究旨在阐明IL-18和IL-1β在MAS发病机制中的作用。
我们建立了一个小鼠模型，在连续7天输注IL-18、IL-1β及其组合后，通过Toll样受体9刺激来评估每种细胞因子的作用。比较IL-18、IL-1β及联合（IL-18+IL-1β）组的症状和实验室检查结果。
IL-1β组和联合组的体重显著下降。所有组均观察到脾肿大，而仅IL-18组出现肝肿大。联合组观察到T细胞数量减少、贫血和血小板减少。IL-18组脾脏中干扰素-γ（IFN-γ）、CXC趋化因子配体9（CXCL9）和IL-12A信使核糖核酸（mRNA）水平上调，IL-10 mRNA水平下调。IL-18组的肝肿大和脾肿大呈剂量依赖性。仅在血浆IL-18水平极高的小鼠中，肿瘤坏死因子-α（TNF-α）、CXCL9和IL-12A mRNA水平上调。
IL-18和IL-1β在MAS发病机制中具有不同作用。对IL-18和IL-1β进行双重阻断可能是治疗MAS所必需的。
