Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells
Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells
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DOI：
10.1111/j.1365-2222.2010.03527.x
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发表时间：
2010-07-01
影响因子：
6.1
通讯作者：
Hizawa, N.
中科院分区：
文献类型：
--
作者：
Kawaguchi, M.;Fujita, J.;Hizawa, N.
Cite this as：M.川口，J. Fujita，F.国分湾大原，黄世康，S. Matsukura，Y.石井，M.阿达奇，H. Satoh和N. Hizawa，Clinical & Experimental Allergy，2010（40）1036- 1043.背景已注意到哮喘患者气道中IL-17 F表达增加，但其在哮喘中的作用尚未完全阐明。胰岛素样生长因子-I（IGF-I）参与气道重塑和炎症反应，但其调节机制尚不清楚。目的进一步阐明IL-17 F的生物学功能。我们研究了IL-17 F是否能够调节支气管上皮细胞中IGF-I的表达。辅助2型细胞因子。向培养物中加入各种激酶抑制剂以鉴定导致IGF-I表达的关键信号事件，结合使用靶向促分裂原和应激活化蛋白激酶（MSK）1、p90核糖体S6激酶（p90 RSK）和环AMP反应元件结合蛋白（CREB）的短干扰RNA（siRNA）。并且与IL-4和IL-13的共刺激增加了其产生。MAP激酶激酶（MEK）抑制剂和Raf 1激酶抑制剂显著抑制IGF-I的产生，PD 98059和Raf 1激酶抑制剂的组合显示出进一步的抑制。过量表达Raf 1和Ras显性负突变体抑制其表达。MSK 1抑制剂显著阻断IL 17 F诱导的IGF-I表达。结论IL-17 F在体外可通过Raf 1-MEK 1/2-ERK 1/2-MSK 1/p90 RSK-CREB途径诱导支气管上皮细胞表达IGF-I。
P>Cite this as: M. Kawaguchi, J. Fujita, F. Kokubu, G. Ohara, S-K Huang, S. Matsukura, Y. Ishii, M. Adachi, H. Satoh and N. Hizawa, Clinical & Experimental Allergy, 2010 (40) 1036-1043.BackgroundIncreased expression of IL-17F has been noted in the airway of asthmatic patients, but its role in asthma has not been fully elucidated. Insulin-like growth factor-I (IGF-I) is known to be involved in airway remodelling and inflammation, while its regulatory mechanisms remain to be defined.ObjectiveTo further clarify the biological function of IL-17F, we investigated whether IL-17F is able to regulate the expression of IGF-I in bronchial epithelial cells.MethodsBronchial epithelial cells were stimulated with IL-17F in the presence or absence of T-helper type 2 cytokines. Various kinase inhibitors were added to the culture to identify the key signalling events leading to the expression of IGF-I, in conjunction with the use of short interfering RNAs (siRNAs) targeting mitogen- and stress-activated protein kinase (MSK) 1, p90 ribosomal S6 kinase (p90RSK), and cyclic AMP response element-binding protein (CREB).ResultsIL-17F significantly induced IGF-I gene and protein expression, and co-stimulation with IL-4 and IL-13 augmented its production. MAP kinase kinase (MEK) inhibitors and the Raf1 kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Raf1 kinase inhibitor showed further inhibition. Overexpression of Raf1 and Ras dominant-negative mutants inhibited its expression. MSK1 inhibitors significantly blocked IL17F-induced IGF-I expression. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked its expression.ConclusionsIn bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB pathway in vitro.