IL-4 receptor signaling in Clara cells is required for allergen-induced mucus production
IL-4 receptor signaling in Clara cells is required for allergen-induced mucus production
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DOI：
10.4049/jimmunol.175.6.3746
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发表时间：
2005-09-15
影响因子：
4.4
通讯作者：
Erle, DJ
中科院分区：
文献类型：
--
作者：
Kuperman, DA;Huang, XZ;Erle, DJ
粘液分泌过多是哮喘的重要病理特征。Th2细胞因子IL-4和IL-13都与变应原诱导的粘液产生、炎症和呼吸道高反应性有关。这两种细胞因子都使用含有IL-4Rα亚单位的受体，这些受体在肺中的许多细胞类型上都有表达。目前还很难确定变应原诱导的粘液产生是否严格依赖于IL-4和IL-13对上皮细胞的直接作用，或者是否存在其他独立的机制。为了解决这个问题，我们使用了一种针对细胞类型的可诱导基因打靶策略，选择性地干扰了Clara细胞中的IL-4ra基因，Clara细胞是一种能够产生粘液的杯状细胞。在OVA致敏和激发后，Clara细胞特异性IL-4Rα缺陷小鼠和对照组小鼠在血清IgE水平、呼吸道炎症细胞数量、Th2细胞因子产生和气道反应性方面表现出相似的升高。然而，与对照组小鼠相比，Clara细胞特异性IL-4Rα缺陷小鼠几乎完全免受过敏原诱导的粘液产生的影响。由于只有IL-13和IL-4被认为通过IL-4Rα传递信号，我们得出结论，IL-4和/或IL-13对Clara细胞的直接作用是过敏原诱导的呼吸道上皮产生粘液所必需的。
Excessive mucus production is an important pathological feature of asthma. The Th2 cytokines IL-4 and IL-13 have both been implicated in allergen-induced mucus production, inflammation, and airway hyperreactivity. Both of these cytokines use receptors that contain the IL-4R alpha subunit, and these receptors are expressed on many cell types in the lung. It has been difficult to determine whether allergen-induced mucus production is strictly dependent on direct effects of IL-4 and IL-13 on epithelial cells or whether other independent mechanisms exist. To address this question, we used a cell type-specific inducible gene-targeting strategy to selectively disrupt the IL-4Ra gene in Clara cells, an airway epithelial cell population that gives rise to mucus-producing goblet cells. Clara cell-specific IL-4R alpha-deficient mice and control mice developed similar elevations in serum IgE levels, airway inflammatory cell numbers, Th2 cytokine production, and airway reactivity following OVA sensitization and challenge. However, compared with control mice, Clara cell-specific IL-4R alpha-deficient mice were nearly completely protected from allergen-induced mucus production. Because only IL-13 and IL-4 are thought to signal via IL-4R alpha, we conclude that direct effects of IL-4 and/or IL-13 on Clara cells are required for allergen-induced mucus production in the airway epithelium.