Department of Medicine, Graduate School of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan.
Int J Mol Med. 2011 Oct;28(4):573-8. doi: 10.3892/ijmm.2011.718. Epub 2011 Jun 8.
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 µg/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 Jag1 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.
白细胞介素 (IL)-33 是一种细胞因子，属于 IL-1 家族。IL-33 在 Th2 免疫反应中发挥重要作用，并诱导肠道黏膜杯状细胞增生。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。通过腹腔内给予 IL-33（1μg/只）每 48 小时一次来诱导 DSS 结肠炎的 BALB/c 小鼠。通过标准免疫组织化学程序评估组织样本。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 [Jagged1 (Jag1) 和 Delta-like (Dll) 1 和 4] 的粘膜 mRNA 表达明显增加。IL-33 在对照小鼠中诱导杯状细胞增生。在 DSS 结肠炎小鼠中，结肠中的杯状细胞被耗尽，但 IL-33 完全防止了 DSS 结肠炎小鼠中杯状细胞的耗竭。IL-33 诱导对照小鼠的 Jag1 和 Dll4 mRNA 表达显著下降。Jag1、Dll1 和 4 的粘膜 mRNA 表达在 DSS 结肠炎小鼠中明显升高，但通过给予 IL-33 显著阻止了这种升高。IL-33 呈剂量依赖性降低小鼠结肠黏膜下肌成纤维细胞中的 Jag1 mRNA 表达。与预防杯状细胞耗竭的作用相反，IL-33 加重了 DSS 结肠炎。IL-33 通过抑制 DSS 结肠炎中 Notch 配体表达来预防杯状细胞耗竭，但加剧了疾病活动。IL-33 在黏膜炎症中发挥两种相反的作用；一种是通过诱导杯状细胞产生的保护作用，另一种是作为 Th2 细胞因子的促炎作用。
