Nozato Kyoko, Fujita Junichi, Kawaguchi Mio, Ohara Gen, Morishima Yuko, Ishii Yukio, Huang Shau-Ku, Kokubu Fumio, Satoh Hiroaki, Hizawa Nobuyuki
Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan.
J Allergy (Cairo). 2011;2011:587204. doi: 10.1155/2011/587204. Epub 2011 Oct 13.
IL-17F plays a crucial role in airway inflammatory diseases including asthma, but its function has not been fully elucidated. CCL20 is also involved in allergic airway inflammation, while its regulatory mechanisms remain to be defined. To further identify a novel role of IL-17F, the expression of CCL20 by IL-17F in bronchial epithelial cells and the signaling mechanisms involved were investigated. Bronchial epithelial cells were stimulated with IL-17F, and the levels of CCL20 gene and protein measured, with the effects of the addition of various kinase inhibitors and siRNAs also investigated. IL-17F significantly induced the expression of CCL20 gene and protein. Pretreatment with inhibitors for MEK1/2, Raf1 and MSK1, and overexpression of a Raf1 dominant-negative mutant significantly diminished IL-17F-induced CCL20 production. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked CCL20 expression. These findings suggest that IL-17F is able to induce CCL20 via Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB signaling pathway in bronchial epithelial cells. The IL-17F/CCL20 axis may be a novel pharmacological target for asthma.
白细胞介素-17F（IL-17F）在包括哮喘在内的气道炎症性疾病中发挥关键作用，但其功能尚未完全阐明。趋化因子配体20（CCL20）也参与过敏性气道炎症，但其调控机制仍有待确定。为了进一步明确IL-17F的新作用，研究了IL-17F在支气管上皮细胞中对CCL20的表达及相关信号传导机制。用IL-17F刺激支气管上皮细胞，检测CCL20基因和蛋白水平，并研究添加各种激酶抑制剂和小干扰RNA（siRNA）的影响。IL-17F显著诱导CCL20基因和蛋白的表达。用MEK1/2、Raf1和MSK1抑制剂预处理，以及Raf1显性负性突变体的过表达显著减少了IL-17F诱导的CCL20产生。此外，转染靶向MSK1、p90核糖体S6激酶（p90RSK）和环磷腺苷效应元件结合蛋白（CREB）的siRNA可阻断CCL20的表达。这些发现表明，IL-17F能够通过Raf1-MEK1/2-细胞外信号调节激酶1/2（ERK1/2）-MSK1/p90RSK-CREB信号通路在支气管上皮细胞中诱导CCL20的产生。IL-17F/CCL20轴可能是哮喘的一个新的药理学靶点。
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