title: IL-17F-induced IL-11 release in bronchial epithelial cells via MSK1-CREB pathway.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Ibaraki 3058575, Japan. mkawaguchi@md.tsukuba.ac.jp
authors.forename: Mio
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujita
authors.forename: Fumio
authors.initials: F
authors.lastname: Kokubu
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Homma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsukura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D001980:Bronchi / Q000166:cytology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D017370:Interleukin-11; D018793:Interleukin-13; D020381:Interleukin-17; D007546:Isoquinolines; D013449:Sulfonamides; D015847:Interleukin-4; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C064758:Ro 31-8220