Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop
Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop
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DOI：
10.1074/jbc.m210429200
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发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Wu, R
中科院分区：
文献类型：
--
作者：
Chen, Y;Thai, P;Wu, R
粘液分泌过多和持续气道炎症是各种气道疾病的共同特征，如哮喘、慢性阻塞性肺疾病和囊性纤维化。一个关键问题是：这些疾病中相关的气道炎症是否影响粘液的产生？如果有，其潜在机制是什么？黏液分泌的增加似乎是由于黏液蛋白基因表达的增加，并且经常伴随着气道上皮黏液细胞数量的增加（杯状细胞增生/化生）。许多关于粘蛋白基因表达的研究都针对Th2细胞因子，如白细胞介素(IL)-4、IL-9和IL-13，因为它们在过敏性气道疾病（如哮喘）中的病理生理作用。然而，这些细胞因子的作用并不一定与它们与气道上皮细胞的直接相互作用有关。在我们的研究中，我们用一组细胞因子（白细胞介素-1 α、1 β、2、3、4、5、6、7、8、9、10、11、12、13、15、16、17、18和肿瘤坏死因子α）处理了高度分化的人气管支气管上皮（TBE）细胞培养物。我们发现IL-6和IL-17可以刺激粘蛋白基因MUC5B和MUC5AC。在我们的实验中，Th2细胞因子IL-4、IL-9和IL-13没有刺激MUC5AC或MUC5B。IL-6和IL-17对原代猴和小鼠TBE细胞MUC5B/ MUC5B表达有类似的刺激作用。对MUC5B表达的进一步研究表明，IL-17的作用至少部分是通过依赖jak2的自分泌/旁分泌回路通过IL-6介导的。最后，有证据表明IL-6和IL-17都通过ERK信号通路介导MUC5B的表达。
Mucus hypersecretion and persistent airway inflammation are common features of various airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. One key question is: does the associated airway inflammation in these diseases affect mucus production? If so, what is the underlying mechanism? It appears that increased mucus secretion results from increased mucin gene expression and is also frequently accompanied by an increased number of mucous cells (goblet cell hyperplasia/metaplasia) in the airway epithelium. Many studies on mucin gene expression have been directed toward Th2 cytokines such as interleukin (IL)-4, IL-9, and IL-13 because of their known pathophysiological role in allergic airway diseases such as asthma. However, the effect of these cytokines has not been definitely linked to their direct interaction with airway epithelial cells. In our study, we treated highly differentiated cultures of primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines (interleukin-1alpha, 1beta, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and tumor necrosis factor alpha). We found that IL-6 and IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. The Th2 cytokines IL-4, IL-9, and IL-13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL-17's effect is at least partly mediated through IL-6 by a JAK2-dependent autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6 and IL-17 mediate MUC5B expression through the ERK signaling pathway.