MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium.
MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium.
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DOI：
10.1152/ajplung.00292.2010
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发表时间：
2011-02
期刊：
影响因子：
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通讯作者：
M. Monzon;R. Forteza;S. Marina Casalino-Matsuda
中科院分区：
文献类型：
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作者：
M. Monzon;R. Forteza;S. Marina Casalino-Matsuda
香烟烟雾是慢性阻塞性肺疾病（COPD）发展的主要危险因素，COPD是与气流阻塞、粘液分泌过多、慢性炎症和炎症介质如单核细胞趋化蛋白-1（MCP-1）的上调相关的呼吸系统疾病。MCP-1通过其受体CCR 2诱导趋化性并激活（44/42）MAPK，MAPK是一种已知在支气管上皮粘蛋白调节中起关键作用的激酶。在本研究中，我们使用正常人支气管上皮（NHBE）细胞的分化原代培养物来测试MCP-1是否通过其受体CCR 2诱导粘蛋白上调。我们提供的证据表明，NHBE细胞释放MCP-1的上皮表面和表达的CCR 2B亚型的受体主要在顶端极。此外，我们发现MCP-1在气道上皮中具有新的功能，增加两种主要的气道粘蛋白MUC 5AC和MUC 5 B，这种作用至少部分地由其受体CCR 2B与小窝中的G（q）亚基相互作用引发的级联事件介导，随后是PLCβ、PKC和（44/42）MAPK激活。我们还表明，MCP-1能够使用相同的受体诱导其自身的表达，但通过不同的途径，涉及RhoA GT3。此外，我们发现单次暴露于MCP-1足以诱导MCP-1分泌并在初始暴露后持续7天的粘蛋白上调，这是由CCR 2B介导的作用，如使用短发夹RNA所证实的。这些结果与我们在吸烟者气道上皮中的数据一致，其中CCR 2B存在于MUC 5AC和MUC 5 B表达细胞中，MCP-1表达增加与MUC 5AC和MUC 5 B免疫标记增加相关，表明本研究中原代细胞培养物中描述的机制在体内有效。因此，靶向MCP-1/CCR 2B的治疗方法不仅可用于预防炎性细胞流入气道，还可用于预防粘液分泌过多和杯状细胞增生。
Cigarette smoke represents a major risk factor for the development of chronic obstructive pulmonary disease (COPD), a respiratory condition associated with airflow obstruction, mucus hypersecretion, chronic inflammation, and upregulation of inflammatory mediators such as the monocyte chemotactic protein-1 (MCP-1). MCP-1 through its receptor CCR2 induces chemotaxis and activates (44/42)MAPK, a kinase known to play a key role in mucin regulation in bronchial epithelium. In the present study we used differentiated primary cultures of normal human bronchial epithelial (NHBE) cells to test whether MCP-1 through its receptor CCR2 induces mucin upregulation. We have provided evidence that NHBE cells release MCP-1 to the epithelial surface and express the CCR2B isoform of the receptor mainly at the apical pole. In addition, we found that MCP-1 has a novel function in airway epithelium, increasing the two major airway mucins MUC5AC and MUC5B, an effect mediated, at least in part, by a cascade of events initiated by interaction of its receptor CCR2B with G(q) subunits in caveolae, followed by PLCβ, PKC, and (44/42)MAPK activation. We also have shown that MCP-1 is able to induce its own expression using the same receptor but through a different pathway that involves RhoA GTPase. Furthermore, we found that a single exposure to MCP-1 is enough to induce MCP-1 secretion and sustained mucin upregulation up to 7 days after initial exposure, an effect mediated by CCR2B as confirmed using short hairpin RNA. These results agree with our data in smoker's airway epithelium, where CCR2B is present in MUC5AC- and MUC5B-expressing cells and augmented MCP-1 expression is associated with increased MUC5AC and MUC5B immunolabeling, suggesting that the mechanisms described in primary cell cultures in the present study are operative in vivo. Therefore, therapeutic approaches targeting MCP-1/CCR2B may be useful in preventing not only influx of inflammatory cells to the airways but also mucus hypersecretion and goblet cell hyperplasia.