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

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Abstract

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
Pages (from-to)1408-1414
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume119
Issue number6
DOIs
Publication statusPublished - Jun 1 2007
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kawaguchi, M., Kokubu, F., Huang, S. K., Homma, T., Odaka, M., Watanabe, S., Suzuki, S., Ieki, K., Matsukura, S., Kurokawa, M., & Adachi, M. (2007). The IL-17F signaling pathway is involved in the induction of IFN-γ-inducible protein 10 in bronchial epithelial cells. Journal of Allergy and Clinical Immunology, 119(6), 1408-1414. https://doi.org/10.1016/j.jaci.2007.02.036