Interleukin-33 suppresses Notch ligand expression and prevents goblet cell depletion in dextran sulfate sodium-induced colitis
Interleukin-33 suppresses Notch ligand expression and prevents goblet cell depletion in dextran sulfate sodium-induced colitis
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DOI：
10.3892/ijmm.2011.718
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Fujiyama, Yoshihide
中科院分区：
文献类型：
--
作者：
Imaeda, Hirotsugu;Andoh, Akira;Fujiyama, Yoshihide
白细胞介素（IL）-33是属于IL-1家族的细胞因子。IL-33在Th 2免疫应答中起重要作用，并诱导肠粘膜中杯状细胞增生。在这项研究中，为了阐明IL-33诱导杯状细胞增生的分子机制，我们研究了IL-33如何调节葡聚糖硫酸钠（DSS）诱导的实验性结肠炎中的Notch信号通路。在BALB/c小鼠中每48小时腹腔内施用IL-33（1 μ g/体）诱导DSS结肠炎。通过标准免疫组织化学程序评价组织样品。通过实时聚合酶链反应分析Notch配体的粘膜mRNA表达。在DSS-结肠炎小鼠中，Notch配体[Jagged 1（Jag 1）和Delta样（Dll）1和4]的粘膜mRNA表达显著增加。对照小鼠中IL-33诱导的杯状细胞增生。在DSS-结肠炎小鼠中，结肠中的杯状细胞被耗尽，但IL-33完全防止DSS-结肠炎小鼠中的杯状细胞耗尽。IL-33诱导对照小鼠粘膜中Jag 1和Dll 4 mRNA表达显著降低。在DSS-结肠炎小鼠中，Jag 1、Dll 1和4的粘蛋白mRNA表达显著升高，但这种升高被IL-33的施用显著阻断。IL-33剂量依赖性地降低小鼠结肠上皮下肌成纤维细胞中Jag 1 mRNA的表达。与其对杯状细胞耗竭的预防作用相反，IL-33加重了DSS结肠炎。IL-33通过其对DSS结肠炎中Notch配体表达的抑制作用防止杯状细胞耗竭，但加剧了疾病活动。IL-33在粘膜炎症中起两种对抗作用;第一种是通过杯状细胞诱导的保护作用，第二种是作为Th 2细胞因子的促炎作用。
Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 plays an important role in Th2 immune responses, and induces goblet cell hyperplasia in the intestinal mucosa. In this study, to elucidate the molecular mechanisms underlying IL-33-induced goblet cell hyperplasia, we investigated how IL-33 modulates the Notch signaling pathway in dextran sulfate sodium (DSS)-induced experimental colitis. DSS colitis was induced in BALB/c mice with intraperitoneal administrations of IL-33 (1 mu g/body) every 48 h. Tissue samples were evaluated by standard immunohistochemical procedures. The mucosal mRNA expression of the Notch ligands was analyzed by a real-time polymerase chain reaction. The mucosal mRNA expression of Notch ligands [Jagged1 (Jag1) and Delta-like (Dll) 1 and 4] was significantly increased in DSS-colitis mice. IL-33-induced goblet cell hyperplasia in the control mice. In the DSS-colitis mice, the goblet cells were depleted in the colon, but IL-33 completely prevented goblet cell depletion in the DSS-colitis mice. IL-33 induced a significant decrease in Jag1 and Dll4 mRNA expression in the mucosa of the control mice. Mucosal mRNA expression for Jag1, Dll1 and 4 was significantly elevated in the DSS-colitis mice, but this elevation was significantly blocked by the administration of IL-33. IL-33 dose-dependently decreased Jag 1 mRNA expression in mouse colonic subepithelial myofibroblasts. In contrast to its preventive effects on goblet cell depletion, IL-33 aggravated DSS colitis. IL-33 prevented goblet cell depletion via its inhibitory actions against Notch ligand expression in DSS colitis, but exacerbated the disease activity. IL-33 plays two counter actions in mucosal inflammation; the first is a protective action via goblet cell induction, and the second is a pro-inflammatory action as a Th2 cytokine.