The IL-17F signaling pathway is involved in the induction of IFN-γ-inducible protein 10 in bronchial epithelial cells

Mio Kawaguchi, Fumio Kokubu, Shau Ku Huang, Tetsuya Homma, Miho Odaka, Shin Watanabe, Shintaro Suzuki, Koushi Ieki, Satoshi Matsukura, Masatsugu Kurokawa, Mitsuru Adachi

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Background: IL-17F is involved in airway inflammation, but its biologic activity and signaling pathway remain incompletely defined. Interferon-γ-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 TH1 cytokine, TH2 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-γ, IL-1β, and TNF-α 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. Conclusion: 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. Clinical implications: The IL-17F-IP-10 axis might be a novel and critical therapeutic target for airway inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)1408-1414
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number6
StatePublished - Jun 2007


  • Extracellular signal-regulated kinase 1/2
  • IL-17F
  • cyclic AMP response element-binding protein
  • interferon-γ-inducible protein 10
  • p90 ribosomal S6 kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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