Intestinal nematode infection induces pulmonary eosinophilia via IL-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intra-nasal administration of a lung extract induced IL-33 production in lungs. Additionally, lung extracts increased Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified retinoblastoma-binding protein 9 (RBBP9) as a major DAMP with IL33ia. RBBP9 was originally discovered as a protein that provides cells with resistance to the growth inhibitory effect of transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce prostaglandin E₂ (PGE₂) that, in turn, induced fibroblasts to produce IL-33. RBBP9-activated fibroblasts expressed mRNAs of cyclooxygenase-2 (COX-2) and PGE₂ synthase-1 that convert arachidonic acid to PGE₂. Furthermore, they expressed PGE₂ receptors E-prostanoid (EP) 2 and EP4. Thus, treatment with a COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced IL-33 production. Nematode infection induced pulmonary Il33 mRNA expression, which was inhibited by the COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that nematode infection induced pulmonary Il33 mRNA via PGE₂. RBBP9 was expressed constitutively in the lung in the steady state, which did not increase after nematode infection. Finally, we found that Rbbp9-deficient mice had a significantly diminished capacity to increase pulmonary Il33 mRNA expression following nematode infection. Thus, the PGE₂-EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary IL-33 production in nematode-infected animals.

中文翻译：

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肺成纤维细胞通过产生前列腺素 E2 响应视网膜母细胞瘤结合蛋白 9 的刺激而产生白细胞介素 33。

肠道线虫感染通过 IL-33 诱导肺嗜酸性粒细胞增多，尽管肺 IL-33 诱导的机制尚不清楚。由于线虫迁移损害肺，我们推测肺源性损伤相关分子模式 (DAMP) 具有诱导 IL-33 的活性 (IL33ia)。事实上，肺提取物的鼻内给药诱导了肺中 IL-33 的产生。此外，肺提取物增加了Il33原代肺成纤维细胞中的 mRNA 表达。蛋白质组学分析将视网膜母细胞瘤结合蛋白 9 (RBBP9) 鉴定为具有 IL33ia 的主要 DAMP。RBBP9 最初是作为一种蛋白质被发现的，它为细胞提供了对转化生长因子 (TGF)-β1 的生长抑制作用的抵抗力。在这里，我们发现 RBBP9 的刺激诱导原代成纤维细胞产生前列腺素 E ₂ (PGE ₂ )，进而诱导成纤维细胞产生 IL-33。RBBP9 激活的成纤维细胞表达环氧合酶-2 (COX-2) 和 PGE ₂合酶-1 的mRNA ，将花生四烯酸转化为 PGE ₂。此外，他们表达了 PGE ₂受体 E-前列腺素 (EP) 2 和 EP4。因此，用 COX-2 抑制剂或 EP2 和/或 EP4 受体拮抗剂治疗抑制了 RBBP9 诱导的 IL-33 产生。线虫感染诱导肺Il33 mRNA 表达，该表达被 COX-2 抑制剂或 EP2 和 EP4 拮抗剂抑制，表明线虫感染通过 PGE ₂诱导肺Il33 mRNA 。RBBP9 在稳定状态下在肺中组成型表达，线虫感染后不增加。最后，我们发现Rbbp9 缺陷小鼠在线虫感染后增加肺Il33 mRNA 表达的能力显着降低。因此，PGE ₂由受损肺释放的 RBBP9 激活的 -EP2/EP4 通路对于线虫感染动物的肺 IL-33 产生很重要。