Kawaguchi Mio, Fujita Junichi, Kokubu Fumio, Huang Shau-Ku, Homma Tetsuya, Matsukura Satoshi, Adachi Mitsuru, Hizawa Nobuyuki
Department of Respiratory Medicine, University of Tsukuba, Ibaraki 3058575, Japan.
Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L804-10. doi: 10.1152/ajplung.90607.2008. Epub 2009 Feb 27.
IL-17F is involved in asthma, but its biological function and signaling pathway have not been fully elucidated. IL-11 is clearly expressed in the airway of patients with allergic airway diseases such as asthma and plays an important role in airway remodeling and inflammation. Therefore, we investigated the expression of IL-11 by IL-17F in bronchial epithelial cells. Bronchial epithelial cells were cultured in the presence or absence of IL-17F and/or Th2 cytokines (IL-4 and IL-13) or various kinase inhibitors to analyze the expression of IL-11. Next, activation of mitogen- and stress-activated protein kinase (MSK) 1 by IL-17F was investigated. Moreover, the effect of short interfering RNAs (siRNAs) targeting MSK1 and cAMP response element binding protein (CREB) on IL-17F-induced IL-11 expression was investigated. IL-17F induced IL-11 expression, whereas the costimulation with IL-4 and IL-13 augmented this effect even further. MEK inhibitors PD-98059, U0126, and Raf1 kinase inhibitor I, significantly inhibited IL-11 production, whereas overexpression of a Raf1 dominant-negative mutant inhibited its expression. IL-17F clearly phosphorylated MSK1, whereas PD-98059 inhibited the phosphorylation of IL-17F-induced MSK1. Both MSK1 inhibitors Ro-31-8220 and H89 significantly blocked IL-11 expression. Moreover, transfection of the cells with siRNAs targeting MSK1 inhibited activation of CREB, and the siRNAs targeting MSK1 and CREB blocked expression of IL-11. These data suggest that IL-17F may be involved in airway inflammation and remodeling via the induction of IL-11, and RafI-MEK1/2-ERK1/2-MSK1-CREB is identified as a novel signaling pathway participating in this process. Therefore, the IL-17F/IL-11 axis may be a valuable therapeutic target for asthma.
白细胞介素-17F（IL-17F）与哮喘有关，但其生物学功能和信号通路尚未完全阐明。白细胞介素-11（IL-11）在哮喘等过敏性气道疾病患者的气道中明显表达，并在气道重塑和炎症中起重要作用。因此，我们研究了IL-17F在支气管上皮细胞中对IL-11表达的影响。在有或无IL-17F和/或Th2细胞因子（IL-4和IL-13）或各种激酶抑制剂的情况下培养支气管上皮细胞，以分析IL-11的表达。接下来，研究了IL-17F对丝裂原和应激激活蛋白激酶（MSK）1的激活作用。此外，还研究了靶向MSK1和环磷酸腺苷反应元件结合蛋白（CREB）的小干扰RNA（siRNA）对IL-17F诱导的IL-11表达的影响。IL-17F诱导IL-11表达，而IL-4和IL-13的共刺激进一步增强了这种作用。MEK抑制剂PD-98059、U0126和Raf1激酶抑制剂I显著抑制IL-11的产生，而Raf1显性负突变体的过表达抑制其表达。IL-17F明显使MSK1磷酸化，而PD-98059抑制IL-17F诱导的MSK1磷酸化。MSK1抑制剂Ro-31-8220和H89均显著阻断IL-11表达。此外，用靶向MSK1的siRNA转染细胞可抑制CREB的激活，而靶向MSK1和CREB的siRNA可阻断IL-11的表达。这些数据表明，IL-17F可能通过诱导IL-11参与气道炎症和重塑，并且RafI-MEK1/2-ERK1/2-MSK1-CREB被确定为参与这一过程的新信号通路。因此，IL-17F/IL-11轴可能是哮喘的一个有价值的治疗靶点。
