title: Interleukin-33 induces interleukin-17F in bronchial epithelial cells.
abstract: BACKGROUND
  IL-33 is clearly expressed in the airway of patients with asthma, but its role in asthma has not yet been fully understood. IL-17F is also involved in the pathogenesis of asthma. However, the regulatory mechanisms of IL-17F expression remain to be defined. To further indentify the role of IL-33 in asthma, we investigated the expression of IL-17F by IL-33 in bronchial epithelial cells and its signaling mechanisms.
  
  
  METHODS
  Bronchial epithelial cells were stimulated with IL-33. The levels of IL-17F expression were analyzed using real-time PCR and ELISA. Next, the involvement of ST2, MAP kinases, and mitogen- and stress-activated protein kinase1 (MSK1) was determined by Western blot analyses. Various kinase inhibitors and anti-ST2 neutralizing Abs were added to the culture to identify the key signaling events leading to the expression of IL-17F, in conjunction with the use of short interfering RNAs (siRNAs) targeting MSK1.
  
  
  RESULTS
  IL-33 significantly induced IL-17F gene and protein expression. The receptor for IL-33, ST2, was expressed in bronchial epithelial cells. Among MAP kinases, IL-33 phosphorylated ERK1/2, but not p38MAPK and JNK. It was inhibited by the pretreatment of anti-ST2 neutralizing (blocking) Abs. MEK inhibitor significantly blocked IL-17F production. Moreover, IL-33 phosphorylated MSK1, and MEK inhibitor diminished its phosphorylation. Finally, MSK1 inhibitors and transfection of the siRNAs targeting MSK1 significantly blocked the IL-17F expression.
  
  
  CONCLUSIONS
  IL-33 induces IL-17F via ST2-ERK1/2-MSK1 signaling pathway in bronchial epithelial cells. These data suggest that the IL-33/IL-17F axis is involved in allergic airway inflammation and may be a novel therapeutic target.
authors.affiliation: Department of Pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: F
authors.initials: F
authors.lastname: Kokubu
authors.forename: G
authors.initials: G
authors.lastname: Ohara
authors.forename: K
authors.initials: K
authors.lastname: Ota
authors.forename: S-K
authors.initials: SK
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Morishima
authors.forename: Y
authors.initials: Y
authors.lastname: Ishii
authors.forename: H
authors.initials: H
authors.lastname: Satoh
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: N
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D001249:Asthma / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D001980:Bronchi / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C440021:IL17F protein, human; C506536:IL33 protein, human; D020381:Interleukin-17; D000067596:Interleukin-33; D007378:Interleukins