title: Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells.
abstract: 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 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. mkawaguchi@md.tsukuba.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: J
authors.initials: J
authors.lastname: Fujita
authors.forename: F
authors.initials: F
authors.lastname: Kokubu
authors.forename: G
authors.initials: G
authors.lastname: Ohara
authors.forename: S-K
authors.initials: SK
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Matsukura
authors.forename: Y
authors.initials: Y
authors.lastname: Ishii
authors.forename: M
authors.initials: M
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Satoh
authors.forename: N
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D015398:Signal Transduction
chemical_list: C440021:IL17F protein, human; D020381:Interleukin-17; D007334:Insulin-Like Growth Factor I