A novel role for murine IL-4 in vivo: Induction of MUCSAC gene expression and mucin hypersecretion
A novel role for murine IL-4 in vivo: Induction of MUCSAC gene expression and mucin hypersecretion
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DOI：
10.1165/ajrcmb.16.4.9115759
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发表时间：
1997-04-01
影响因子：
6.4
通讯作者：
Rankin, JA
中科院分区：
文献类型：
--
作者：
Temann, UA;Prasad, B;Rankin, JA
粘液过度分泌和下呼吸道呼吸道堵塞导致与哮喘相关的发病率和死亡率。白介素4在某些形式的哮喘中起着推定作用。因此，选择在肺内高表达小鼠IL-4的转基因小鼠，研究IL-4对粘液糖蛋白基因表达和粘蛋白释放的影响。对IL-4小鼠肺切片的组织学检查显示，来自导气管的非纤毛上皮细胞肥大，至少部分原因是粘液糖蛋白的积累。这些细胞的胞浆用粘液胺、阿尔辛蓝(AB)和高碘酸席夫(PAS)染色呈阳性。纤毛细胞也被放大，但没有显示任何粘蛋白特异性染色。在对照小鼠的非纤毛(Clara)细胞中发现的包涵体颗粒在IL-4转基因小鼠中缺失。对肺组织总RNA的Northern印迹分析表明，与转基因阴性对照相比，IL-4转基因小鼠肺组织中MUC5AC基因的表达明显增强，而MUC2基因的表达没有明显上调。此外，与转基因阴性对照相比，IL-4过度表达的小鼠灌洗液中AB和PAS阳性物质的数量增加了5到10倍。因此，IL-4在肺内局部的过度表达通过改变基因表达来促进粘液糖蛋白的合成，导致粘液糖蛋白在非纤毛上皮细胞中积聚，并诱导粘液释放到气道腔内。因此，我们推测，在一些哮喘患者中看到的粘液过度产生可能是炎症肺内IL-4作用的直接结果。
Mucus hypersecretion and plugging of lower respiratory tract airways contributes to the morbidity and mortality associated with asthma. Interleukin (IL)-4 plays a putative role in some forms of asthma. Thus, transgenic mice that overexpress murine IL-4 selectively within the lung were used to study the effect of IL-4 on mucus glycoprotein gene expression and mucin release. Histologic examination of lung sections from IL-4 mice revealed that nonciliated epithelial cells from conducting airways were hypertrophic, due at least in part to the accumulation of mucus glycoprotein. The cytoplasm of these cells stained positively for glycoproteins using mucicarmine, alcian blue (AB), and periodic acid-Schiff (PAS). Ciliated cells were also enlarged but did not show any mucin-specific staining. Inclusion granules typically found in nonciliated (Clara) cells of control mice were absent in the IL-4 transgenic mice. Northern blot analysis of total RNA from lung tissue revealed that the expression of the MUC5AC, but not MUC2, mucin gene was distinctly upgraded in IL-4 transgenic mice compared to transgene-negative controls. In addition, a 5- to 10-fold increase in AB- and PAS-positive material was found in lavage fluid from IL-4 overexpressing mice compared to transgene-negative controls. Thus, the overexpression of IL-4 locally within the lung enhances mucus glycoprotein synthesis by altering gene expression, results in the accumulation of mucus glycoprotein in nonciliated epithelial cells, and induces the release of mucus into the airway lumen. We therefore hypothesize that the overproduction of mucus seen in some patients with asthma may be a direct result of the action of IL-4 within the inflamed lung.