title: The IL-17F signaling pathway is involved in the induction of IFN-gamma-inducible protein 10 in bronchial epithelial cells.
abstract: BACKGROUND
  IL-17F is involved in airway inflammation, but its biologic activity and signaling pathway remain incompletely defined. Interferon-gamma-inducible protein 10 (IP-10) is widely expressed and plays a role in airway inflammatory diseases.
  
  
  OBJECTIVE
  We sought to investigate the functional linkage between IL-17F and IP-10 expression in bronchial epithelial cells.
  
  
  METHODS
  Bronchial epithelial cells were cultured in the presence or absence of IL-17F, and/or a T(H)1 cytokine, T(H)2 cytokines, proinflammatory cytokines, various kinase inhibitors, or a Raf1 dominant-negative mutant to analyze the expression of IP-10. Moreover, the involvement of p90 ribosomal S6 kinase (p90RSK) and cyclic AMP response element-binding protein (CREB) in IL-17F-induced IP-10 expression were investigated.
  
  
  RESULTS
  IL-17F induces the gene and protein expression of IP-10. The addition of IFN-gamma, IL-1beta, and TNF-alpha augmented IL-17F-induced IP-10 expression. The mitogen-activated protein kinase kinase (MEK) inhibitors PD98059, U0126, and Raf1 kinase inhibitor I significantly inhibited its production. In contrast, a p38 inhibitor, a JNK inhibitor, protein kinase C inhibitors, and a phosphatidylinositol 3-kinase inhibitor, showed no inhibitory effect. Furthermore, overexpression of a Raf1 dominant-negative mutant inhibited its expression. Of interest, IL-17F phosphorylated p90RSK and CREB, and transfection of the cells with a short interfering RNA for p90RSK or CREB inhibited its expression, suggesting p90RSK and CREB as novel signaling molecules of IL-17F.
  
  
  CONCLUSIONS
  IL-17F is a potent inducer of IP-10 in bronchial epithelial cells through the activation of the Raf1-MEK1/2-extracellular signal-regulated kinase 1/2-p90RSK-CREB pathway, supporting its regulatory role in airway inflammation.
  
  
  CONCLUSIONS
  The IL-17F-IP-10 axis might be a novel and critical therapeutic target for airway inflammatory diseases.
authors.affiliation: First Department of Internal Medicine, Showa University School of Medicine, Tokyo. miokawguchi@aol.com
authors.forename: Mio
authors.initials: M
authors.lastname: Kawaguchi
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: Miho
authors.initials: M
authors.lastname: Odaka
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Koushi
authors.initials: K
authors.lastname: Ieki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsukura
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
mesh_terms: D001980:Bronchi / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D004847:Epithelial Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology
chemical_list: D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D017362:Cyclic AMP Response Element-Binding Protein; C440021:IL17F protein, human; D020381:Interleukin-17; D007371:Interferon-gamma; D019908:Proto-Oncogene Proteins c-raf; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases