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Induction of insulin-like growth factor-l by interleukin-17F in bronchial epithelial cells

机译：白介素-17F在支气管上皮细胞中诱导胰岛素样生长因子-1

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Background Increased 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.Objective To 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.Methods Bronchial 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). Results IL-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 Rafl kinase inhibitor significantly inhibited IGF-I production, and the combination of PD98059 and Rafl kinase inhibitor showed further inhibition. Overexpression of Rafl 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.Conclusions In bronchial epithelial cells, IL-17F is able to induce the expression of IGF-I via the Rafl-MEKl/2-ERKl/2-MSKl/p90RSK-CREB pathway in vitro.
机译：背景技术在哮喘患者的气道中已经注意到IL-17F的表达增加，但尚未完全阐明其在哮喘中的作用。胰岛素样生长因子-I（IGF-I）参与气道重塑和炎症，但其调节机制尚待确定。目的为进一步阐明IL-17F的生物学功能，我们研究了IL-17F是否方法在存在或不存在2型T辅助细胞因子的刺激下，用IL-17F刺激支气管上皮细胞。将多种激酶抑制剂添加到培养物中以鉴定导致IGF-1表达的关键信号事件，并结合使用靶向有丝分裂原和应激激活蛋白激酶（MSK）1，p90的短干扰RNA（siRNA）核糖体S6激酶（p90RSK）和环状AMP反应元件结合蛋白（CREB）。结果IL-17F显着诱导了IGF-1基因和蛋白质的表达，与IL-4和IL-13的共同刺激增加了其产生。 MAP激酶激酶（MEK）抑制剂和Raf1激酶抑制剂显着抑制了IGF-1的产生，PD98059和Raf1激酶抑制剂的组合显示出进一步的抑制作用。 Rafl和Ras显性负突变体的过表达抑制了其表达。 MSK1抑制剂可显着阻断IL17F诱导的IGF-1的表达。此外，靶向MSK1，p90RSK和CREB的siRNA的转染会阻止其表达。结论在支气管上皮细胞中，IL-17F能够通过Rafl-MEK1 / 2 / ERK1 / 2 / MSK1 /诱导IGF-1的表达。 p90RSK-CREB体外途径。

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