Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
J Immunol. 2010 Nov 15;185(10):5743-50. doi: 10.4049/jimmunol.0903818. Epub 2010 Oct 6.
IL-33 is a member of the IL-1 family and mediates its biological effects via the ST2 receptor, which is selectively expressed on Th2 cells and mast cells. Although polymorphic variation in ST2 is strongly associated with asthma, it is currently unclear whether IL-33 acts directly on lung tissue cells at sites of airway remodeling. Therefore, we aimed to identify the IL-33-responsive cells among primary human lung tissue cells. ST2 mRNA was expressed in both endothelial and epithelial cells but not in fibroblasts or smooth muscle cells. Correspondingly, IL-33 promoted IL-8 production by both endothelial and epithelial cells but not by fibroblasts or smooth muscle cells. Transfection of ST2 small interference RNA into both endothelial and epithelial cells significantly reduced the IL-33-dependent upregulation of IL-8, suggesting that IL-33-mediated responses in these cells occur via the ST2 receptor. Importantly, Th2 cytokines, such as IL-4, further enhanced ST2 expression and function in both endothelial and epithelial cells. The IL-33-mediated production of IL-8 by epithelial cells was almost completely suppressed by corticosteroid treatment. In contrast, the effect of corticosteroid treatment on the IL-33-mediated responses of endothelial cells was only partial. IL-33 induced activation of both ERK and p38 MAPK in endothelial cells but only ERK in epithelial cells. p38 MAPK was required for the IL-33-mediated responses of endothelial cells, whereas ERK was required for IL-33-mediated IL-8 production by epithelial cells. Taken together, these findings suggest that IL-33-mediated inflammatory responses of lung tissue cells may be involved in the chronic allergic inflammation of the asthmatic airway.
白细胞介素 33（IL-33）是白细胞介素 1 家族的成员，通过 ST2 受体介导其生物学效应，ST2 受体选择性表达于 Th2 细胞和肥大细胞上。虽然 ST2 的多态性变异与哮喘强烈相关，但目前尚不清楚 IL-33 是否直接作用于气道重塑部位的肺组织细胞。因此，我们旨在鉴定原代人肺组织细胞中对 IL-33 有反应的细胞。ST2mRNA 在内皮细胞和上皮细胞中表达，但不在成纤维细胞或平滑肌细胞中表达。相应地，IL-33 促进内皮细胞和上皮细胞产生白细胞介素 8（IL-8），但不促进成纤维细胞或平滑肌细胞产生 IL-8。ST2 小干扰 RNA 转染到内皮细胞和上皮细胞中均显著降低了 IL-33 依赖性的 IL-8 上调，表明 IL-33 在这些细胞中的介导反应是通过 ST2 受体发生的。重要的是，Th2 细胞因子，如白细胞介素 4（IL-4），进一步增强了内皮细胞和上皮细胞中 ST2 的表达和功能。皮质类固醇治疗几乎完全抑制了上皮细胞中由 IL-33 介导的 IL-8 产生。相比之下，皮质类固醇治疗对内皮细胞中由 IL-33 介导的反应的影响只是部分的。IL-33 在内皮细胞中诱导 ERK 和 p38MAPK 的激活，但仅在上皮细胞中诱导 ERK 的激活。p38MAPK 是内皮细胞中 IL-33 介导的反应所必需的，而 ERK 是上皮细胞中由 IL-33 介导的 IL-8 产生所必需的。总之，这些发现表明肺组织细胞中由 IL-33 介导的炎症反应可能参与哮喘气道的慢性过敏性炎症。
