Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, exhibits both pro-inflammatory and pro-homeostatic properties depending on the context and tissues in which it is expressed. It remains unknown whether TSLP has a similar dual role in the airways, where TSLP is known to promote allergic inflammation. Here we show that TSLP receptor (TSLPR)-deficient mice (Tslpr-/-) and mice treated with anti-TSLP antibodies exhibited increased airway inflammation and morbidity rates after bleomycin-induced tissue damage. We found that signaling through TSLPR on non-hematopoietic cells was sufficient for TSLP's protective function. Consistent with this finding, we showed that TSLP reduces caspase-1 and caspase-3 activity levels in primary human bronchial epithelial cells treated with bleomycin via Bcl-xL up-regulation. These observations were recapitulated in vivo by observing that Tslpr-/- mice showed reduced Bcl-xL expression that paralleled increased lung caspase-1 and caspase-3 activity levels and IL-1β concentrations in the bronchial-alveolar lavage fluid. Our studies reveal a novel contribution for TSLP in preventing damage-induced airway inflammation.

中文翻译：

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胸腺基质淋巴细胞生成素通过调节 caspase-1 活性和抑制细胞凋亡在气道损伤和炎症模型中起到保护作用。

胸腺基质淋巴细胞生成素 (TSLP) 是一种上皮细胞衍生的细胞因子，根据其表达的环境和组织表现出促炎和促稳态特性。目前尚不清楚 TSLP 是否在气道中具有类似的双重作用，已知 TSLP 会促进过敏性炎症。在这里，我们显示 TSLP 受体 (TSLPR) 缺陷小鼠 (Tslpr-/-) 和用抗 TSLP 抗体治疗的小鼠在博来霉素诱导的组织损伤后表现出增加的气道炎症和发病率。我们发现通过非造血细胞上的 TSLPR 发出的信号足以实现 TSLP 的保护功能。与这一发现一致，我们发现 TSLP 通过 Bcl-xL 上调降低了用博来霉素处理的原代人支气管上皮细胞中的 caspase-1 和 caspase-3 活性水平。通过观察 Tslpr-/- 小鼠显示 Bcl-xL 表达降低，这与支气管肺泡灌洗液中肺 caspase-1 和 caspase-3 活性水平和 IL-1β 浓度的增加平行，这些观察结果在体内得到了概括。我们的研究揭示了 TSLP 在预防损伤引起的气道炎症方面的新贡献。